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Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways
Advances in Biological Regulation xxx (2017) 1e8
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Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways Fumio Sakane a, *, Satoru Mizuno a, Daisuke Takahashi a, Hiromichi Sakai b a
Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 September 2017 Received in revised form 8 September 2017 Accepted 8 September 2017 Available online xxx
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprises ten isozymes (aek) and regulates a wide variety of physiological and pathological events, such as cancer, type II diabetes, neuronal disorders and immune responses. DG and PA consist of various molecular species that have different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain at least 50 structurally distinct DG/PA species. Because DGK is one of the components of phosphatidylinositol (PI) turnover, the generally accepted dogma is that all DGK isozymes utilize 18:0/20:4-DG derived from PI turnover. We recently established a specific liquid chromatography-mass spectrometry method to analyze which PA species were generated by DGK isozymes in a cell stimulationdependent manner. Interestingly, we determined that DGKd, which is closely related to the pathogenesis of type II diabetes, preferentially utilized 14:0/16:0-, 14:0/16:1-, 16:0/ 16:0-, 16:0/16:1-, 16:0/18:0- and 16:0/18:1-DG species (X:Y ¼ the total number of carbon atoms: the total number of double bonds) supplied from the phosphatidylcholine-specific phospholipase C pathway, but not 18:0/20:4-DG, in high glucose-stimulated C2C12 myoblasts. Moreover, DGKa mainly consumed 14:0/16:0-, 16:0/18:1-, 18:0/18:1- and 18:1/18:1DG species during cell proliferation in AKI melanoma cells. Furthermore, we found that 16:0/16:0-PA was specifically produced by DGKz in Neuro-2a cells during retinoic acidand serum starvation-induced neuronal differentiation. These results indicate that DGK isozymes utilize a variety of DG molecular species derived from PI turnover-independent pathways as substrates in different stimuli and cells. DGK isozymes phosphorylate various DG species to generate various PA species. It was revealed that the modes of activation of conventional and novel protein kinase isoforms by DG molecular species varied considerably. However, PA species-selective binding proteins have not been found to date. Therefore, we next attempted to identify PA species-selective binding proteins from the mouse brain and identified a-synuclein, which has causal links to Parkinson's disease. Intriguingly, we determined that among phospholipids, including several PA species (16:0/16:0-PA, 16:0/18:1-PA, 18:1/18:1-PA, 18:0/18:0-PA and 18:0/20:4PA); 18:1/18:1-PA was the most strongly bound PA to a-synuclein. Moreover, 18:1/18:1-PA
Keywords: Diacylglycerol kinase Phosphatidic acid Monoacylglycerol kinase Lysophosphatidic acid Phosphatidylinositol turnover Phosphatidylcholine-specific phospholipase Cancer Diabetes Parkinson's disease
Abbreviations: DG, diacylglycerol; DGK, diacylglycerol kinase; GRP, guanylnucleotide-releasing protein; KO, knockout; LC, liquid chromatography; LPA, lyso-phosphatidic acid; MG, monoacylglycerol; MGK, monoacylglycerol kinase; MS, mass spectrometry; PA, phosphatidic acid; PC, phosphatidylcholine; PI, phosphatidylinositol; PLC, phospholipase C; PKC, protein kinase C; PS, phosphatidylserine. * Corresponding author. Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. E-mail address: [email protected] (F. Sakane). http://dx.doi.org/10.1016/j.jbior.2017.09.003 2212-4926/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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strongly enhanced secondary structural changes from the random coil form to the a-helix form and generated a multimeric and proteinase K-resistant a-synuclein protein. In contrast with the dogma described above, our recent studies strongly suggest that PI turnover-derived DG species and also various DG species derived from PI turnoverindependent pathways are utilized by DGK isozymes. DG species supplied from distinct pathways may be utilized by DGK isozymes based on different stimuli present in different types of cells, and individual PA molecular species would have specific targets and exert their own physiological functions. © 2017 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of a liquid chromatography-mass spectrometry method to improve detection of PA species detection . . . . . . .. . . . . . . DG species utilized by DGK isozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. DG species utilized by DGKd in C2C12 myoblasts stimulated with high glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. DG species utilized by DGKa in growing AKI melanoma cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. DG species utilized by DGKz in Neuro-2a neuroblastoma cells during neuronal differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting of individual DG and PA molecular species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. DG species-selective targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. PA species-selective targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-Monoacylglycerol (MG) kinase (MGK) and 2-MGK activities of DGK isozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA) (Baldanzi, 2014; Goto et al., 2006; Merida et al., 2008; Sakane et al., 2007; Topham and Epand, 2009). To date, ten mammalian DGK isozymes, a, b, g, d, ε, z, h, q, i and k, have been identified (Fig. 1). Moreover, several alternative splicing productsdsuch as d1 and d2 (Sakane et al., 2002); h1eh4 (Murakami et al., 2003, 2016; Shionoya et al., 2015); z1 and z2 (Ding et al., 1997); and i1ei3 (Ito et al., 2004)dhave also been found. These isozymes are subdivided into five groups, type I (a, b and g), II (d, h and k), III (ε), IV (z and i) and V (q), according to structural features (Fig. 1) (Baldanzi, 2014; Goto et al., 2006; Merida et al., 2008; Sakane et al., 2007; Topham and Epand, 2009). Each group is characterized by subtype-specific functional domains, such as EF-hand motifs (type I), pleckstrin homology and sterile a motif domains (type II), ankyrin repeats (type IV) and a ras-associating domain (type V) (Fig. 1). DGK isozymes regulate a wide variety of physiological and pathological events (Sakane et al., 2007, 2016, 2008). For example, type I DGKa, which is activated in a calcium-dependent manner (Sakane et al., 1990, 1991), is involved in a wide variety of pathophysiological events, such as T-cell anergy induction (Olenchock et al., 2006; Zha et al., 2006), cell motility and invasion (Cutrupi et al., 2000; Rainero et al., 2014), and cancer cell growth/apoptosis (Takeishi et al., 2012; Torres-Ayuso et al., 2014; Yanagisawa et al., 2007). Therefore, a selective and potent inhibitor for DGKa (Liu et al., 2016) can be an ideal anticancer drug candidate that attenuates cancer cell proliferation and simultaneously enhances immune responses, including anti-cancer immunity. Knockout (KO) mice of DGKb exhibited bipolar disorder (mania)-like phenotypes (Kakefuda et al., 2010; Shirai et al., 2010). DGKg regulated lamellipodium formation (Tsushima et al., 2004), antigen-induced mast cell degranulation (Sakuma et al., 2014) and insulin secretion (Kurohane Kaneko et al., 2013). DGKd positively regulated epidermal growth factor receptor signaling (Crotty et al., 2006), and DGKd deficiency also caused hyperglycemia-induced peripheral insulin resistance and thereby exacerbated the severity of type II diabetes (Chibalin et al., 2008). In addition, brain-specific conditional DGKd-KO mice showed obsessive compulsive disorder-like behaviors (Usuki et al., 2016). DGKh acts as a critical regulator of B-Raf/C-Raf-dependent cell proliferation (Yasuda et al., 2009), and DGKh-deficient mice demonstrated bipolar disorder (mania)-like phenotypes (Isozaki et al., 2016). DGKk is implicated in fragile X syndrome (Tabet et al., 2016). DGKε regulates seizure susceptibility and long-term potentiation (Rodriguez De Turco et al., 2001). DGKz negatively regulates T-cell response (Zhong et al., 2003). In addition, DGKz is involved in the maintenance of spine density (Kim et al., 2009) and reciprocally regulates p53 and nuclear factor-kB (Tanaka et al., 2013, 2016; Tsuchiya et al., 2015). DGKi inhibits Ras guanylnucleotide-releasing protein (GRP) 3-dependent-Rap1 signaling (Regier et al., 2005). DGKq is suggested to be
Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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Fig. 1. Mammalian DGK family proteins. MARCKS: myristoylated alanine-rich C-kinase substrate; PH: pleckstrin homology; RA: Ras-associated; RVH: recoverin homology; SAM: sterile a-motif.
associated with susceptibility to Parkinson's disease by genome-wide association studies (Pankratz et al., 2009; SimonSanchez et al., 2011). DG and PA consist of various molecular species with different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain more than 50 structurally distinct DG/PA species. DGK is a component of PI turnover and initiates PI regeneration (Hodgkin et al., 1998) (Fig. 2). This fact generated a dogma that all DGK isozymes utilize 18:0/20:4-DG (X:Y ¼ the total number of carbon atoms: the total number of double bonds), which is derived from PI turnover. In this context, DGKε indeed utilizes 18:0/20:4-DG in vitro and in vivo (Rodriguez De Turco et al., 2001; Shulga et al., 2011; Tang et al., 1996) (Fig. 2). However, nine other DGK isozymes failed to exhibit substrate selectivity for 18:0/20:4-DG in vitro. Thus, we questioned whether these nine isozymes indeed utilize 18:0/20:4-DG species in cells. Although several reports addressed this question (Pettitt and Wakelam, 1999; Van der Bend et al., 1994), the answer is still unclear because those studies used exogenously
Fig. 2. Various new DG phosphorylation pathways that are independent of PI turnover. PIP2: phosphatidylinositol 4,5-bisphosphate.
Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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generated/added DG species and overexpressed DGK isozymes, which are probably distributed at random apart from their original locations. It is likely that the enzymes metabolized DG species under such non-physiological conditions. Therefore, to address this question more convincingly, we quantitatively detected cell stimulation- and endogenous DGK isozymedependent changes in PA molecular species, which are minor components of phospholipids in cells. However, it has been difficult to quantitatively determine small changes in PA species levels in physiological and pathological events. 2. Development of a liquid chromatography-mass spectrometry method to improve detection of PA species detection Liquid chromatography-mass spectrometry (LC-MS) is a powerful tool to detect different molecular species of phospholipids in cells (Houjou et al., 2005; Pulfer and Murphy, 2003). However, there were still problems detecting PA molecular species using LC-MS. Because PA is a minor component of phospholipids and contains a variety of fatty acids, extensively broad PA peaks inevitably overlap with other major phospholipid peaks, causing ion suppression, which leads to inferior detection, quantification and reproducibility. Therefore, we optimized LC conditions using a silica column LC and mobile phases containing high concentrations of ammonia (Mizuno et al., 2012). To test the developed LC-MS method, we examined phospholipid mixtures from various mammalian cells and confirmed that PA species from m/z 591.41 (14:0/14:0-PA) to m/z 759.59 (18:0/22:0-PA) were quantitatively and reproducibly detected. 3. DG species utilized by DGK isozymes 3.1. DG species utilized by DGKd in C2C12 myoblasts stimulated with high glucose Type II diabetes afflicted over 400 million people worldwide in 2015. The characteristic features of type II diabetes include insulin resistance, glucose intolerance, hyperglycemia and, often, hyperinsulinemia (Biddinger and Kahn, 2006). Glucoseinduced insulin resistance is associated with a temporal increase in the intracellular DG mass in skeletal muscle (Kraegen et al., 2006). DGKd is highly expressed in skeletal muscle (Sakane et al., 1996), which is a major insulin target organ for glucose disposal (DeFronzo et al., 1981). Chibalin et al. demonstrated that DGKd regulates glucose uptake and that a decrease in DGKd expression resulted in the aggravation of type II diabetes (Chibalin et al., 2008). Increasing amounts of DG caused increased phosphorylation of protein kinase C (PKC) d and a decrease in the expression of the insulin receptor and insulin receptor substrate-1 proteins involved in insulin signaling (Chibalin et al., 2008). Moreover, Miele et al. reported that short-term exposure to high glucose (within 5 min) increased DGKd activity in skeletal muscle cells, followed by a reduction of PKCa activity and transactivation of the insulin receptor signal (Miele et al., 2007). Hence, these studies indicate that DG consumed by DGKd during high glucose exposure is a key regulator of glucose uptake in skeletal muscle cells. We investigated changes in PA species produced in glucose-stimulated C2C12 myoblasts using our newly developed LCMS method (Mizuno et al., 2012) to identify DG species metabolized by DGKd under acute high glucose conditions (5 min). Interestingly, the LC-MS analyses indicated that DGKd preferably metabolized some DG molecular species, 14:0/16:0-, 14:0/ 16:1-, 16:0/16:0-, 16:0/16:1-, 16:0/18:0- and 16:0/18:1-DG, but not DG species containing arachidonic acid (18:0/20:4-DG), in response to high glucose stimulation (Sakai et al., 2014). Moreover, the production of these DG species was suppressed by a phosphatidylcholine (PC)-specific phospholipase C (PLC) inhibitor, D609. Therefore, these DG species were suggested to be produced and supplied by PC-PLC-dependent PC hydrolysis, indicating an unexpected linkage between PC-PLC and DGKd. It is known that D609 inhibits sphingomyelin synthase in addition to PC-PLC (Luberto and Hannun, 1998). Therefore, we cannot rule out the possibility that DGKd partly utilizes sphingomyelin synthase-dependent DG. However, it is likely that DGKd phosphorylates DG species generated, at least in part, by PC-PLC because the co-immunoprecipitates with DGKd2 contained PC-PLC activity (Sakai et al., 2014). Although the activity of PC-PLC was first identified more than 30 years ago, the molecular identity (gene) remains unclear (Adibhatla et al., 2012). As described above, our study revealed that DGKd2 directly or indirectly associated with PC-PLC (Sakai et al., 2014). Using the pull-down of PC-PLC activity with DGKd2 may help identify the PC-PLC enzyme using proteomics approaches. Therefore, DGKd2 may serve as a good tool to search for the molecular identity of PC-PLC. 3.2. DG species utilized by DGKa in growing AKI melanoma cells The overexpression of DGKa-D1e196, a constitutively active mutant, strongly increased the amounts of 16:0/16:1-, 16:0/ 18:1-, 18:0/18:1- and 18:1/18:1-PA, which were sensitive to a new DGKa-selective inhibitor CU-3, in COS-7 cells (Liu et al., 2016). DGKa acts as an anti-apoptotic factor and enhances proliferation in cancer cells (Takeishi et al., 2012; Yanagisawa et al., 2007). Similar to COS-7 cells overexpressing DGKa-D1e196, the study with siRNA knockdown of DGKa demonstrated that DGKa mainly consumed 14:0/16:0-, 16:0/18:1-, 18:0/18:1- and 18:1/18:1-DG species, but not 18:0/20:4-DG, during cell proliferation in AKI melanoma cells (Akiyama et al., unpublished work). Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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3.3. DG species utilized by DGKz in Neuro-2a neuroblastoma cells during neuronal differentiation Several previous reports demonstrated that the amount of PA was increased during neuronal differentiation (Traynor, 1984; Traynor et al., 1982). However, which PA species are generated has not been explored. We identified the PA species generated during retinoic acid (RA)-induced neuroblastoma cell differentiation. Intriguingly, the abundance of 16:0/16:0-PA species was dramatically and transiently increased in Neuro-2a neuroblastoma cells 24e48 h after RA-treatment (Mizuno et al., 2016). In addition, 14:0/16:0- and 16:0/18:0-PA species were also moderately increased. Similar results were also obtained when Neuro-2a cells were differentiated for 24 h by serum starvation. The silencing of DGKz expression significantly decreased the production of 16:0/16:0-PA species. Moreover, neurite outgrowth was also markedly attenuated by the deficiency of DGKz. Taken together, these results indicate that DGKz exclusively generates very restricted PA species, 16:0/16:0PA, and up-regulates neurite outgrowth during the initial/early stage of neuroblastoma cell differentiation. Taken together, DGKd, a and z utilize different DG molecular species, probably supplied by distinct pathways independent of the PI turnover, and have distinct and diverse DG supply pathways. The different linkages to DG supply pathways may be due to distinct subcellular localization and/or protein-protein interaction of DGKd, a and z. 4. Targeting of individual DG and PA molecular species 4.1. DG species-selective targets As described above, various DG molecular species are consumed by corresponding DGK isozymes. Conventional (a, bII and g) and novel (d, ε, h and q) protein kinase C (PKC) isoforms are known to be activated by DG (Hurley et al., 1997; Newton, 2009; Nishizuka, 1992; Ron and Kazanietz, 1999; Zeng et al., 2012). However, comprehensive analyses have not been performed. We recently analyzed the activation of the PKC isozymes in the presence of 2e2000 mmol% 16:0/16:0-, 16:0/18:1-, 18:1/18:1-, 18:0/20:4- or 18:0/22:6-DG species (Kamiya et al., 2016). PKCa activity was strongly increased by DG and exhibited a less preference for 18:0/22:6-DG at 2 mmol%. PKCbII activity was moderately enhanced by DG and did not show a significant preference for DG species. PKCg was moderately activated by DG and exhibited a moderate preference for 18:0/22:6-DG at 2 mmol%. PKCd activity was moderately augmented by DG and had a preference for 18:0/22:6-DG at 20 and 200 mmol%. PKCε activity moderately increased by DG and showed a moderate preference for 18:0/22:6-DG at 2000 mmol%. PKCh was not significantly activated by DG. PKCq was the most strongly activated by DG and demonstrated a preference for 18:0/22:6-DG at 2 and 20 mmol% DG. These results suggest that conventional and novel PKCs have different sensitivities and dependencies on DG and a distinct preference for shorter DG species containing saturated fatty acids and longer DG species containing polyunsaturated fatty acids. Therefore, the modes of activation of conventional PKC and novel PKC isozymes by DG molecular species varied considerably in vitro. This differential regulation may be important for their physiological functions. It is also possible that distinct DG molecular species consumed by various DGK isozymes may differentially activate conventional and novel PKC isoforms. 4.2. PA species-selective targets As described above, various PA molecular species are produced by different DGK isozymes. It was reported that the dissociation of the DEP domain-containing mammalian target of rapamycin-interacting protein from the mammalian target of rapamycin complex 1 was induced by PA species containing unsaturated fatty acids, which were produced by phospholipase D (Yoon et al., 2015). However, PA species-selective binding proteins have been almost never identified to date. Thus, as a first attempt, we tried to identify PA species-selective binding proteins from mouse brain using a screening method with 16:0/16:0-PA-containing liposome precipitation and MS/MS analysis. Intriguingly, we found that a-synuclein bound to 16:0/ 16:0-PA (Mizuno et al., 2017). a-Synuclein has been implicated in Parkinson's disease (Ruiperez et al., 2010), because asynuclein is the primary component of Lewy bodies in patients with the disease (Spillantini et al., 1997). a-Synuclein binds to vesicles containing acidic phospholipids, such as phosphatidylserine (PS) and PA, and PS binds to a-synuclein with almost the same affinity as PA (Davidson et al., 1998; Jiang et al., 2015). However, these studies generally used only 16:0/18:1-PA because this species is abundant in the brain. Thus, the effects of different acyl chain compositions of PA species on the interaction with a-synuclein are poorly understood. Therefore, we characterized the binding activities of a-synuclein using several PA species, including 16:0/16:0-PA, 16:0/18:1-PA, 18:1/18:1-PA, 18:0/18:0-PA and 18:0/20:4-PA (Fig. 3). Intriguingly, among these PA species, 18:1/18:1-PA bound most strongly to the a-synuclein protein (Mizuno et al., 2017) (Fig. 3). Moreover, the binding activity of 18:1/18:1-PA was considerably higher than that of 18:1/18:1-PS. 18:1/18:1-PA strongly induced secondary structural changes, from random coils to a-helices. Furthermore, 18:1/18:1-PA more markedly accelerated the generation of multimeric and proteinase K-resistant a-synuclein, compared to 16:0/18:1-PA (Mizuno et al., 2017) (Fig. 3). These results indicate that among phospholipids examined to date, 18:1/18:1-PA demonstrates the strongest binding to a-synuclein as well as the most effective enhancement of its secondary structural changes (from random coils to a-helices) and aggregate formation (Mizuno et al., 2017) (Fig. 3). Interestingly, single nucleotide polymorphisms (rs1564282, rs11248060) of DGKQ (DGKq gene) have been associated with the risk of Parkinson's disease (Pankratz et al., 2009; Simon-Sanchez et al., 2011). Moreover, DGKq is highly expressed in the cerebellum and hippocampus in the adult rat brain (Houssa et al., 1997). Furthermore, overexpression of DGKq primarily Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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Fig. 3. 18:1/18:1-PA selectively binds to a-synuclein (Protein Data Bank ID:1XQ8) and strongly induces its a-helix formation and aggregation.
increased the amount of 18:1/18:1-PA in mouse primary hepatocytes (Zhang et al., 2015). Therefore, these results imply that abnormal aggregation of a-synuclein results from 18:1/18:1-PA production by DGKq in the brain. In our first attempt, a-synuclein was identified by screening using the 16:0/16:0-PA liposome and mouse brain. Screenings with liposomes containing other PA species and other tissues and cells would identify additional PA molecular speciesselective binding proteins. 5. 1-Monoacylglycerol (MG) kinase (MGK) and 2-MGK activities of DGK isozymes We have recently revealed that type I DGKs (a, b and g), type II DGKs (d, h and k) and type III DGK (ε) have 8e19% 2-MGK activity, which produces 2-lysoPA (LPA), compared to their DGK activities in vitro, whereas their 1-MGK activities were less than 3% (Sato et al., 2016). Both the 2-MGK and 1-MGK activities of the type IV DGKs (z and i) were less than 1% of the corresponding DGK activity. Interestingly, the type V DGKq has approximately 6% 1-MGK activity, which generates 1-LPA, and less than 2% 2-MGK activity, compared to DGK activity. These results indicate that the ten DGK isozymes are more enzymatically diverse than expected, and demonstrate a new aspect of DGK. The simultaneous production of PA molecular species with/without 1-LPA or 2-LPA adds complexity to products and may be important to maximize a variety of physiological functions of DGKs. 6. Conclusion Unlike the dogma described above, our recent studies strongly suggest that DGK isozymes utilize not only PI turnoverderived DG species but also various DG species derived from pathways independent of PI turnover. Different DG species supplied form distinct pathways may be utilized by different DGK isozymes based on different stimuli present in different types of cells, and individual PA/DG molecular species would have specific targets and exert their own physiological functions. The DG supply pathways probably determine apparent DG species selectivity of DGK isozymes (DGKa, b, g, d, h, k, z, i and q) that show no selectivity against substrate (DG species) in vitro. There may be various new and unknown DG supply pathways that are independent of the PI turnover. It is possible that exploring new and unknown DG supply pathways and PA speciesselective binding proteins bring us to a new lipid world. Competing interests There are no competing interests for any of the authors. Acknowledgments We thank all members of the Sakane Lab for discussion and suggestions. This work was supported in part by Grants-in-Aid from The Ministry of Education, Culture, Sports, Science and Technology of Japan (FS). KAKENHI Grant Numbers 22370047 (Grant-in-Aid for Scientific Research (B)), 23116505 (Grant-in-Aid for Scientific Research on Innovative Areas), 25116704 Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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(Grant-in-Aid for Scientific Research on Innovative Areas), 26291017 (Grant-in-Aid for Scientific Research (B)), and 15K14470 (Grant-in-Aid for Challenging Exploratory Research), 17H03650 (Grant-in-Aid for Scientific Research (B)).
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Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways Fumio Sakane a, *, Satoru Mizuno a, Daisuke Takahashi a, Hiromichi Sakai b a
Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 September 2017 Received in revised form 8 September 2017 Accepted 8 September 2017 Available online xxx
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprises ten isozymes (aek) and regulates a wide variety of physiological and pathological events, such as cancer, type II diabetes, neuronal disorders and immune responses. DG and PA consist of various molecular species that have different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain at least 50 structurally distinct DG/PA species. Because DGK is one of the components of phosphatidylinositol (PI) turnover, the generally accepted dogma is that all DGK isozymes utilize 18:0/20:4-DG derived from PI turnover. We recently established a specific liquid chromatography-mass spectrometry method to analyze which PA species were generated by DGK isozymes in a cell stimulationdependent manner. Interestingly, we determined that DGKd, which is closely related to the pathogenesis of type II diabetes, preferentially utilized 14:0/16:0-, 14:0/16:1-, 16:0/ 16:0-, 16:0/16:1-, 16:0/18:0- and 16:0/18:1-DG species (X:Y ¼ the total number of carbon atoms: the total number of double bonds) supplied from the phosphatidylcholine-specific phospholipase C pathway, but not 18:0/20:4-DG, in high glucose-stimulated C2C12 myoblasts. Moreover, DGKa mainly consumed 14:0/16:0-, 16:0/18:1-, 18:0/18:1- and 18:1/18:1DG species during cell proliferation in AKI melanoma cells. Furthermore, we found that 16:0/16:0-PA was specifically produced by DGKz in Neuro-2a cells during retinoic acidand serum starvation-induced neuronal differentiation. These results indicate that DGK isozymes utilize a variety of DG molecular species derived from PI turnover-independent pathways as substrates in different stimuli and cells. DGK isozymes phosphorylate various DG species to generate various PA species. It was revealed that the modes of activation of conventional and novel protein kinase isoforms by DG molecular species varied considerably. However, PA species-selective binding proteins have not been found to date. Therefore, we next attempted to identify PA species-selective binding proteins from the mouse brain and identified a-synuclein, which has causal links to Parkinson's disease. Intriguingly, we determined that among phospholipids, including several PA species (16:0/16:0-PA, 16:0/18:1-PA, 18:1/18:1-PA, 18:0/18:0-PA and 18:0/20:4PA); 18:1/18:1-PA was the most strongly bound PA to a-synuclein. Moreover, 18:1/18:1-PA
Keywords: Diacylglycerol kinase Phosphatidic acid Monoacylglycerol kinase Lysophosphatidic acid Phosphatidylinositol turnover Phosphatidylcholine-specific phospholipase Cancer Diabetes Parkinson's disease
Abbreviations: DG, diacylglycerol; DGK, diacylglycerol kinase; GRP, guanylnucleotide-releasing protein; KO, knockout; LC, liquid chromatography; LPA, lyso-phosphatidic acid; MG, monoacylglycerol; MGK, monoacylglycerol kinase; MS, mass spectrometry; PA, phosphatidic acid; PC, phosphatidylcholine; PI, phosphatidylinositol; PLC, phospholipase C; PKC, protein kinase C; PS, phosphatidylserine. * Corresponding author. Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. E-mail address: [email protected] (F. Sakane). http://dx.doi.org/10.1016/j.jbior.2017.09.003 2212-4926/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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strongly enhanced secondary structural changes from the random coil form to the a-helix form and generated a multimeric and proteinase K-resistant a-synuclein protein. In contrast with the dogma described above, our recent studies strongly suggest that PI turnover-derived DG species and also various DG species derived from PI turnoverindependent pathways are utilized by DGK isozymes. DG species supplied from distinct pathways may be utilized by DGK isozymes based on different stimuli present in different types of cells, and individual PA molecular species would have specific targets and exert their own physiological functions. © 2017 Elsevier Ltd. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of a liquid chromatography-mass spectrometry method to improve detection of PA species detection . . . . . . .. . . . . . . DG species utilized by DGK isozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. DG species utilized by DGKd in C2C12 myoblasts stimulated with high glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. DG species utilized by DGKa in growing AKI melanoma cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. DG species utilized by DGKz in Neuro-2a neuroblastoma cells during neuronal differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting of individual DG and PA molecular species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. DG species-selective targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. PA species-selective targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-Monoacylglycerol (MG) kinase (MGK) and 2-MGK activities of DGK isozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA) (Baldanzi, 2014; Goto et al., 2006; Merida et al., 2008; Sakane et al., 2007; Topham and Epand, 2009). To date, ten mammalian DGK isozymes, a, b, g, d, ε, z, h, q, i and k, have been identified (Fig. 1). Moreover, several alternative splicing productsdsuch as d1 and d2 (Sakane et al., 2002); h1eh4 (Murakami et al., 2003, 2016; Shionoya et al., 2015); z1 and z2 (Ding et al., 1997); and i1ei3 (Ito et al., 2004)dhave also been found. These isozymes are subdivided into five groups, type I (a, b and g), II (d, h and k), III (ε), IV (z and i) and V (q), according to structural features (Fig. 1) (Baldanzi, 2014; Goto et al., 2006; Merida et al., 2008; Sakane et al., 2007; Topham and Epand, 2009). Each group is characterized by subtype-specific functional domains, such as EF-hand motifs (type I), pleckstrin homology and sterile a motif domains (type II), ankyrin repeats (type IV) and a ras-associating domain (type V) (Fig. 1). DGK isozymes regulate a wide variety of physiological and pathological events (Sakane et al., 2007, 2016, 2008). For example, type I DGKa, which is activated in a calcium-dependent manner (Sakane et al., 1990, 1991), is involved in a wide variety of pathophysiological events, such as T-cell anergy induction (Olenchock et al., 2006; Zha et al., 2006), cell motility and invasion (Cutrupi et al., 2000; Rainero et al., 2014), and cancer cell growth/apoptosis (Takeishi et al., 2012; Torres-Ayuso et al., 2014; Yanagisawa et al., 2007). Therefore, a selective and potent inhibitor for DGKa (Liu et al., 2016) can be an ideal anticancer drug candidate that attenuates cancer cell proliferation and simultaneously enhances immune responses, including anti-cancer immunity. Knockout (KO) mice of DGKb exhibited bipolar disorder (mania)-like phenotypes (Kakefuda et al., 2010; Shirai et al., 2010). DGKg regulated lamellipodium formation (Tsushima et al., 2004), antigen-induced mast cell degranulation (Sakuma et al., 2014) and insulin secretion (Kurohane Kaneko et al., 2013). DGKd positively regulated epidermal growth factor receptor signaling (Crotty et al., 2006), and DGKd deficiency also caused hyperglycemia-induced peripheral insulin resistance and thereby exacerbated the severity of type II diabetes (Chibalin et al., 2008). In addition, brain-specific conditional DGKd-KO mice showed obsessive compulsive disorder-like behaviors (Usuki et al., 2016). DGKh acts as a critical regulator of B-Raf/C-Raf-dependent cell proliferation (Yasuda et al., 2009), and DGKh-deficient mice demonstrated bipolar disorder (mania)-like phenotypes (Isozaki et al., 2016). DGKk is implicated in fragile X syndrome (Tabet et al., 2016). DGKε regulates seizure susceptibility and long-term potentiation (Rodriguez De Turco et al., 2001). DGKz negatively regulates T-cell response (Zhong et al., 2003). In addition, DGKz is involved in the maintenance of spine density (Kim et al., 2009) and reciprocally regulates p53 and nuclear factor-kB (Tanaka et al., 2013, 2016; Tsuchiya et al., 2015). DGKi inhibits Ras guanylnucleotide-releasing protein (GRP) 3-dependent-Rap1 signaling (Regier et al., 2005). DGKq is suggested to be
Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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Fig. 1. Mammalian DGK family proteins. MARCKS: myristoylated alanine-rich C-kinase substrate; PH: pleckstrin homology; RA: Ras-associated; RVH: recoverin homology; SAM: sterile a-motif.
associated with susceptibility to Parkinson's disease by genome-wide association studies (Pankratz et al., 2009; SimonSanchez et al., 2011). DG and PA consist of various molecular species with different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain more than 50 structurally distinct DG/PA species. DGK is a component of PI turnover and initiates PI regeneration (Hodgkin et al., 1998) (Fig. 2). This fact generated a dogma that all DGK isozymes utilize 18:0/20:4-DG (X:Y ¼ the total number of carbon atoms: the total number of double bonds), which is derived from PI turnover. In this context, DGKε indeed utilizes 18:0/20:4-DG in vitro and in vivo (Rodriguez De Turco et al., 2001; Shulga et al., 2011; Tang et al., 1996) (Fig. 2). However, nine other DGK isozymes failed to exhibit substrate selectivity for 18:0/20:4-DG in vitro. Thus, we questioned whether these nine isozymes indeed utilize 18:0/20:4-DG species in cells. Although several reports addressed this question (Pettitt and Wakelam, 1999; Van der Bend et al., 1994), the answer is still unclear because those studies used exogenously
Fig. 2. Various new DG phosphorylation pathways that are independent of PI turnover. PIP2: phosphatidylinositol 4,5-bisphosphate.
Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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generated/added DG species and overexpressed DGK isozymes, which are probably distributed at random apart from their original locations. It is likely that the enzymes metabolized DG species under such non-physiological conditions. Therefore, to address this question more convincingly, we quantitatively detected cell stimulation- and endogenous DGK isozymedependent changes in PA molecular species, which are minor components of phospholipids in cells. However, it has been difficult to quantitatively determine small changes in PA species levels in physiological and pathological events. 2. Development of a liquid chromatography-mass spectrometry method to improve detection of PA species detection Liquid chromatography-mass spectrometry (LC-MS) is a powerful tool to detect different molecular species of phospholipids in cells (Houjou et al., 2005; Pulfer and Murphy, 2003). However, there were still problems detecting PA molecular species using LC-MS. Because PA is a minor component of phospholipids and contains a variety of fatty acids, extensively broad PA peaks inevitably overlap with other major phospholipid peaks, causing ion suppression, which leads to inferior detection, quantification and reproducibility. Therefore, we optimized LC conditions using a silica column LC and mobile phases containing high concentrations of ammonia (Mizuno et al., 2012). To test the developed LC-MS method, we examined phospholipid mixtures from various mammalian cells and confirmed that PA species from m/z 591.41 (14:0/14:0-PA) to m/z 759.59 (18:0/22:0-PA) were quantitatively and reproducibly detected. 3. DG species utilized by DGK isozymes 3.1. DG species utilized by DGKd in C2C12 myoblasts stimulated with high glucose Type II diabetes afflicted over 400 million people worldwide in 2015. The characteristic features of type II diabetes include insulin resistance, glucose intolerance, hyperglycemia and, often, hyperinsulinemia (Biddinger and Kahn, 2006). Glucoseinduced insulin resistance is associated with a temporal increase in the intracellular DG mass in skeletal muscle (Kraegen et al., 2006). DGKd is highly expressed in skeletal muscle (Sakane et al., 1996), which is a major insulin target organ for glucose disposal (DeFronzo et al., 1981). Chibalin et al. demonstrated that DGKd regulates glucose uptake and that a decrease in DGKd expression resulted in the aggravation of type II diabetes (Chibalin et al., 2008). Increasing amounts of DG caused increased phosphorylation of protein kinase C (PKC) d and a decrease in the expression of the insulin receptor and insulin receptor substrate-1 proteins involved in insulin signaling (Chibalin et al., 2008). Moreover, Miele et al. reported that short-term exposure to high glucose (within 5 min) increased DGKd activity in skeletal muscle cells, followed by a reduction of PKCa activity and transactivation of the insulin receptor signal (Miele et al., 2007). Hence, these studies indicate that DG consumed by DGKd during high glucose exposure is a key regulator of glucose uptake in skeletal muscle cells. We investigated changes in PA species produced in glucose-stimulated C2C12 myoblasts using our newly developed LCMS method (Mizuno et al., 2012) to identify DG species metabolized by DGKd under acute high glucose conditions (5 min). Interestingly, the LC-MS analyses indicated that DGKd preferably metabolized some DG molecular species, 14:0/16:0-, 14:0/ 16:1-, 16:0/16:0-, 16:0/16:1-, 16:0/18:0- and 16:0/18:1-DG, but not DG species containing arachidonic acid (18:0/20:4-DG), in response to high glucose stimulation (Sakai et al., 2014). Moreover, the production of these DG species was suppressed by a phosphatidylcholine (PC)-specific phospholipase C (PLC) inhibitor, D609. Therefore, these DG species were suggested to be produced and supplied by PC-PLC-dependent PC hydrolysis, indicating an unexpected linkage between PC-PLC and DGKd. It is known that D609 inhibits sphingomyelin synthase in addition to PC-PLC (Luberto and Hannun, 1998). Therefore, we cannot rule out the possibility that DGKd partly utilizes sphingomyelin synthase-dependent DG. However, it is likely that DGKd phosphorylates DG species generated, at least in part, by PC-PLC because the co-immunoprecipitates with DGKd2 contained PC-PLC activity (Sakai et al., 2014). Although the activity of PC-PLC was first identified more than 30 years ago, the molecular identity (gene) remains unclear (Adibhatla et al., 2012). As described above, our study revealed that DGKd2 directly or indirectly associated with PC-PLC (Sakai et al., 2014). Using the pull-down of PC-PLC activity with DGKd2 may help identify the PC-PLC enzyme using proteomics approaches. Therefore, DGKd2 may serve as a good tool to search for the molecular identity of PC-PLC. 3.2. DG species utilized by DGKa in growing AKI melanoma cells The overexpression of DGKa-D1e196, a constitutively active mutant, strongly increased the amounts of 16:0/16:1-, 16:0/ 18:1-, 18:0/18:1- and 18:1/18:1-PA, which were sensitive to a new DGKa-selective inhibitor CU-3, in COS-7 cells (Liu et al., 2016). DGKa acts as an anti-apoptotic factor and enhances proliferation in cancer cells (Takeishi et al., 2012; Yanagisawa et al., 2007). Similar to COS-7 cells overexpressing DGKa-D1e196, the study with siRNA knockdown of DGKa demonstrated that DGKa mainly consumed 14:0/16:0-, 16:0/18:1-, 18:0/18:1- and 18:1/18:1-DG species, but not 18:0/20:4-DG, during cell proliferation in AKI melanoma cells (Akiyama et al., unpublished work). Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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3.3. DG species utilized by DGKz in Neuro-2a neuroblastoma cells during neuronal differentiation Several previous reports demonstrated that the amount of PA was increased during neuronal differentiation (Traynor, 1984; Traynor et al., 1982). However, which PA species are generated has not been explored. We identified the PA species generated during retinoic acid (RA)-induced neuroblastoma cell differentiation. Intriguingly, the abundance of 16:0/16:0-PA species was dramatically and transiently increased in Neuro-2a neuroblastoma cells 24e48 h after RA-treatment (Mizuno et al., 2016). In addition, 14:0/16:0- and 16:0/18:0-PA species were also moderately increased. Similar results were also obtained when Neuro-2a cells were differentiated for 24 h by serum starvation. The silencing of DGKz expression significantly decreased the production of 16:0/16:0-PA species. Moreover, neurite outgrowth was also markedly attenuated by the deficiency of DGKz. Taken together, these results indicate that DGKz exclusively generates very restricted PA species, 16:0/16:0PA, and up-regulates neurite outgrowth during the initial/early stage of neuroblastoma cell differentiation. Taken together, DGKd, a and z utilize different DG molecular species, probably supplied by distinct pathways independent of the PI turnover, and have distinct and diverse DG supply pathways. The different linkages to DG supply pathways may be due to distinct subcellular localization and/or protein-protein interaction of DGKd, a and z. 4. Targeting of individual DG and PA molecular species 4.1. DG species-selective targets As described above, various DG molecular species are consumed by corresponding DGK isozymes. Conventional (a, bII and g) and novel (d, ε, h and q) protein kinase C (PKC) isoforms are known to be activated by DG (Hurley et al., 1997; Newton, 2009; Nishizuka, 1992; Ron and Kazanietz, 1999; Zeng et al., 2012). However, comprehensive analyses have not been performed. We recently analyzed the activation of the PKC isozymes in the presence of 2e2000 mmol% 16:0/16:0-, 16:0/18:1-, 18:1/18:1-, 18:0/20:4- or 18:0/22:6-DG species (Kamiya et al., 2016). PKCa activity was strongly increased by DG and exhibited a less preference for 18:0/22:6-DG at 2 mmol%. PKCbII activity was moderately enhanced by DG and did not show a significant preference for DG species. PKCg was moderately activated by DG and exhibited a moderate preference for 18:0/22:6-DG at 2 mmol%. PKCd activity was moderately augmented by DG and had a preference for 18:0/22:6-DG at 20 and 200 mmol%. PKCε activity moderately increased by DG and showed a moderate preference for 18:0/22:6-DG at 2000 mmol%. PKCh was not significantly activated by DG. PKCq was the most strongly activated by DG and demonstrated a preference for 18:0/22:6-DG at 2 and 20 mmol% DG. These results suggest that conventional and novel PKCs have different sensitivities and dependencies on DG and a distinct preference for shorter DG species containing saturated fatty acids and longer DG species containing polyunsaturated fatty acids. Therefore, the modes of activation of conventional PKC and novel PKC isozymes by DG molecular species varied considerably in vitro. This differential regulation may be important for their physiological functions. It is also possible that distinct DG molecular species consumed by various DGK isozymes may differentially activate conventional and novel PKC isoforms. 4.2. PA species-selective targets As described above, various PA molecular species are produced by different DGK isozymes. It was reported that the dissociation of the DEP domain-containing mammalian target of rapamycin-interacting protein from the mammalian target of rapamycin complex 1 was induced by PA species containing unsaturated fatty acids, which were produced by phospholipase D (Yoon et al., 2015). However, PA species-selective binding proteins have been almost never identified to date. Thus, as a first attempt, we tried to identify PA species-selective binding proteins from mouse brain using a screening method with 16:0/16:0-PA-containing liposome precipitation and MS/MS analysis. Intriguingly, we found that a-synuclein bound to 16:0/ 16:0-PA (Mizuno et al., 2017). a-Synuclein has been implicated in Parkinson's disease (Ruiperez et al., 2010), because asynuclein is the primary component of Lewy bodies in patients with the disease (Spillantini et al., 1997). a-Synuclein binds to vesicles containing acidic phospholipids, such as phosphatidylserine (PS) and PA, and PS binds to a-synuclein with almost the same affinity as PA (Davidson et al., 1998; Jiang et al., 2015). However, these studies generally used only 16:0/18:1-PA because this species is abundant in the brain. Thus, the effects of different acyl chain compositions of PA species on the interaction with a-synuclein are poorly understood. Therefore, we characterized the binding activities of a-synuclein using several PA species, including 16:0/16:0-PA, 16:0/18:1-PA, 18:1/18:1-PA, 18:0/18:0-PA and 18:0/20:4-PA (Fig. 3). Intriguingly, among these PA species, 18:1/18:1-PA bound most strongly to the a-synuclein protein (Mizuno et al., 2017) (Fig. 3). Moreover, the binding activity of 18:1/18:1-PA was considerably higher than that of 18:1/18:1-PS. 18:1/18:1-PA strongly induced secondary structural changes, from random coils to a-helices. Furthermore, 18:1/18:1-PA more markedly accelerated the generation of multimeric and proteinase K-resistant a-synuclein, compared to 16:0/18:1-PA (Mizuno et al., 2017) (Fig. 3). These results indicate that among phospholipids examined to date, 18:1/18:1-PA demonstrates the strongest binding to a-synuclein as well as the most effective enhancement of its secondary structural changes (from random coils to a-helices) and aggregate formation (Mizuno et al., 2017) (Fig. 3). Interestingly, single nucleotide polymorphisms (rs1564282, rs11248060) of DGKQ (DGKq gene) have been associated with the risk of Parkinson's disease (Pankratz et al., 2009; Simon-Sanchez et al., 2011). Moreover, DGKq is highly expressed in the cerebellum and hippocampus in the adult rat brain (Houssa et al., 1997). Furthermore, overexpression of DGKq primarily Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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Fig. 3. 18:1/18:1-PA selectively binds to a-synuclein (Protein Data Bank ID:1XQ8) and strongly induces its a-helix formation and aggregation.
increased the amount of 18:1/18:1-PA in mouse primary hepatocytes (Zhang et al., 2015). Therefore, these results imply that abnormal aggregation of a-synuclein results from 18:1/18:1-PA production by DGKq in the brain. In our first attempt, a-synuclein was identified by screening using the 16:0/16:0-PA liposome and mouse brain. Screenings with liposomes containing other PA species and other tissues and cells would identify additional PA molecular speciesselective binding proteins. 5. 1-Monoacylglycerol (MG) kinase (MGK) and 2-MGK activities of DGK isozymes We have recently revealed that type I DGKs (a, b and g), type II DGKs (d, h and k) and type III DGK (ε) have 8e19% 2-MGK activity, which produces 2-lysoPA (LPA), compared to their DGK activities in vitro, whereas their 1-MGK activities were less than 3% (Sato et al., 2016). Both the 2-MGK and 1-MGK activities of the type IV DGKs (z and i) were less than 1% of the corresponding DGK activity. Interestingly, the type V DGKq has approximately 6% 1-MGK activity, which generates 1-LPA, and less than 2% 2-MGK activity, compared to DGK activity. These results indicate that the ten DGK isozymes are more enzymatically diverse than expected, and demonstrate a new aspect of DGK. The simultaneous production of PA molecular species with/without 1-LPA or 2-LPA adds complexity to products and may be important to maximize a variety of physiological functions of DGKs. 6. Conclusion Unlike the dogma described above, our recent studies strongly suggest that DGK isozymes utilize not only PI turnoverderived DG species but also various DG species derived from pathways independent of PI turnover. Different DG species supplied form distinct pathways may be utilized by different DGK isozymes based on different stimuli present in different types of cells, and individual PA/DG molecular species would have specific targets and exert their own physiological functions. The DG supply pathways probably determine apparent DG species selectivity of DGK isozymes (DGKa, b, g, d, h, k, z, i and q) that show no selectivity against substrate (DG species) in vitro. There may be various new and unknown DG supply pathways that are independent of the PI turnover. It is possible that exploring new and unknown DG supply pathways and PA speciesselective binding proteins bring us to a new lipid world. Competing interests There are no competing interests for any of the authors. Acknowledgments We thank all members of the Sakane Lab for discussion and suggestions. This work was supported in part by Grants-in-Aid from The Ministry of Education, Culture, Sports, Science and Technology of Japan (FS). KAKENHI Grant Numbers 22370047 (Grant-in-Aid for Scientific Research (B)), 23116505 (Grant-in-Aid for Scientific Research on Innovative Areas), 25116704 Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003
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(Grant-in-Aid for Scientific Research on Innovative Areas), 26291017 (Grant-in-Aid for Scientific Research (B)), and 15K14470 (Grant-in-Aid for Challenging Exploratory Research), 17H03650 (Grant-in-Aid for Scientific Research (B)).
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Please cite this article in press as: Sakane, F., et al., Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways, Advances in Biological Regulation (2017), http://dx.doi.org/10.1016/j.jbior.2017.09.003