- Email: [email protected]
Complement C3 and Autophagy Keep the β Cell Alive
Cell Metabolism
Previews is downstream of the profibrogenic platelet-derived growth factor (PDGF), and loss of fibrosis in the absence of STAT-1 in HSCs could occur due to reduced PDGF-mediated HSC activation (Gandhi, 2017). Some studies in STAT-1deficient mice have found increased fibrosis and proposed that STAT-1 inhibits HSC proliferation, but these were in the CCl4 toxin model rather than a NASH model (Jeong et al., 2006). There may be additional indirect effects due to reduced inflammation and liver injury, with the subsequent reduction in profibrogenic signals from damaged hepatocytes. The recognized role of STAT-3 inhibitors in a range of cancers has resulted in a number of strategies to block STAT-3 activity, including peptides, peptidomimetics, small molecule inhibitors, and knockdown approaches, and a number are in clinical trials (Furqan et al., 2013). There has been much less interest in STAT-1 inhibitors, but the current work suggests that such inhibition may be a strategy for the treatment of NASH.
REFERENCES Abe, M., Yoshida, T., Akiba, J., Ikezono, Y., Wada, F., Masuda, A., Sakaue, T., Tanaka, T., Iwamoto, H., Nakamura, T., et al. (2017). STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. World J. Gastroenterol. 23, 6833–6844. Diehl, A.M., and Day, C. (2017). Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N. Engl. J. Med. 377, 2063–2072. Fatemipour, M., Arabzadeh, S.A.M., Molaei, H., Geramizadeh, B., Dabiri, S., Fatemipour, B., Vahedi, S.M., and Malekpour Afshar, R. (2017). Evaluation of STAT3 rs1053004 single nucleotide polymorphism in patients with chronic hepatitis B and hepatocellular carcinoma. Cell. Mol. Biol. 63, 45–50. Furqan, M., Akinleye, A., Mukhi, N., Mittal, V., Chen, Y., and Liu, D. (2013). STAT inhibitors for cancer therapy. J. Hematol. Oncol. 6, 90. Gandhi, C.R. (2017). Hepatic stellate cell activation and pro-fibrogenic signals. J. Hepatol. 67, 1104–1105. Grohmann, M., Wiede, F., Dodd, G.T., Gurzov, E.N., Ooi, G.J., Butt, T., Rasmiena, A.A., Kaur, S., Gulati, T., Goh, P.K., et al. (2018). Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 175, 1289–1306.e20.
Hong, F., Jaruga, B., Kim, W.H., Radaeva, S., El-Assal, O.N., Tian, Z., Nguyen, V.A., and Gao, B. (2002). Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J. Clin. Invest. 110, 1503–1513. Jeong, W.I., Park, O., Radaeva, S., and Gao, B. (2006). STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity. Hepatology 44, 1441–1451. Kim, W.H., Hong, F., Radaeva, S., Jaruga, B., Fan, S., and Gao, B. (2003). STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G761–G768. Kulik, L., and El-Serag, H.B. (2018). Epidemiology and management of hepatocellular carcinoma. Gastroenterology. Published online October 24, 2018. https://doi.org/10.1053/j.gastro.2018.08.065. Masarone, M., Rosato, V., Dallio, M., Gravina, A.G., Aglitti, A., Loguercio, C., Federico, A., and Persico, M. (2018). Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid. Med. Cell. Longev. 2018, 9547613. Stine, J.G., Wentworth, B.J., Zimmet, A., Rinella, M.E., Loomba, R., Caldwell, S.H., and Argo, C.K. (2018). Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment. Pharmacol. Ther. 48, 696–703.
Complement C3 and Autophagy Keep the b Cell Alive Miriam Toledo1,2 and Rajat Singh1,2,3,4,5,* 1Department
of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA 3Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA 4Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA 5The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY 10461, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.12.010 2Department
Autophagy prevents pancreatic b cell death during obesity, although the mechanism of autophagy activation in the b cell has remained elusive. In this issue of Cell Metabolism, King et al. (2018) show that intracellular complement component C3 interacts with autophagy protein ATG16L1 and protects against b cell death by stimulating autophagy. Autophagy is a conserved ‘‘in-bulk’’ lysosomal quality control pathway that degrades cytoplasmic components with precision and selectivity—aged or damaged organelles are eliminated while intact organelles are spared. Given its ability to degrade both proteins and organelles, the impact of autophagy failure on cell function is significant, and the pancre-
atic b cell is no exception. However, the mechanisms that trigger autophagy in pancreatic b cells have remained elusive. In this work, King et al. (2018 [this issue of Cell Metabolism]) reveal an exciting new link between inflammatory pathways and cytoprotective autophagy in b cells, which could help develop strategies to prevent b cell loss during obesity.
4 Cell Metabolism 29, January 8, 2019 ª 2018 Elsevier Inc.
The evidence highlighting the role of autophagy in b cell function comes from studies showing that compensatory expansion of b cells during obesity requires autophagy, and that absence of autophagy impairs insulin secretion and glucose intolerance (Ebato et al., 2008; Jung et al., 2008). In fact, loss of autophagy revealed tell-tale signs of impaired
Cell Metabolism
Previews quality control, i.e., ‘‘balloonthat C3, and not its cleaved products, like’’ degeneration of b cells, interacts with ATG16L1. During autop62 inclusions, and damaged phagy, ATG16L1 binds to ATG12mitochondria (Ebato et al., ATG5 conjugate to generate a heter2008; Jung et al., 2008). This led otrimeric E3 ligase for light-chain 3 to the question—what triggers b (LC3) lipidation, a key step in autocell autophagy during obesity? phagosome formation. Given this Interestingly, starvation, a wellinformation, the authors tested established stimulus for autowhether C3 is required for autophagy phagy, fails to induce autophagy in insulin-secreting rat INS-1 cells. in b cells in vivo (Ebato et al., Autophagy flux analyses in C32008). Since obesity associates depleted cells (C3 / ) showed a remarkable suppression of autowith increased circulating lipid, phagy and accumulation of p62 aginvestigations have since gregates, which are degraded by focused on establishing a causal autophagy. Autophagy also turns link between free fatty acids over insulin granules via crinophagy (FFAs) and autophagy. While (Marsh et al., 2007), and in keeping FFAs stimulate autophagy in with this notion, C3 / b cells disrat-derived INS-1 b cells in culplayed an accumulation of insulin ture (Ebato et al., 2008), whether that resulted in increased insulin FFAs directly stimulate b cell secretion when C3 / b cells were autophagy in vivo remains unsubjected to glucose stimulation. tested. Furthermore, while Increased insulin secretion is likely obesity and lipid accumulation an early effect of C3 depletion in suppress autophagy in liver cultured b cells, and it is conceivable (Singh et al., 2009; Yang et al., that sustained loss of C3 in mice will 2010), b cell autophagy is gradually dampen insulin secretion remarkably induced in obese Figure 1. Islet-Intrinsic Complement C3 Expression as has been observed in b cell-spemice (Ebato et al., 2008), pointing Regulates Autophagy and Prevents b Cell Death cific autophagy gene Atg7-deficient to yet-unknown b cell-intrinsic Obesity-induced cytokines induce C3 gene expression in islets. Cell-intrinsic C3 protein interacts with autophagy protein ATG16L1 mice (Ebato et al., 2008; Jung et al., factors that stimulate autophagy to drive autophagy that protects b cells from apoptosis under 2008). Importantly, given that autoduring stress. diabetogenic conditions. IAPP, islet amyloid polypeptide. phagy mitigates cellular stress, the Enter complement C3—a authors then tested whether C3 deficomponent of the conserved innate immune system and a key humoral no increases were observed in expres- ciency and autophagy failure sensitizes mediator of inflammation, which has sion of receptors for active products of INS-1 cells to death under diabetogenic recently been shown to exhibit non-ca- C3 cleavage or factors known to regulate conditions. Indeed, C3 / b cells, as well nonical functions in cell survival (Liszewski C3 cleavage, suggesting that C3 may it- as those depleted of Atg7, each showed et al., 2013). Since increased C3 expres- self impact b cell function—an interesting marked increase in apoptosis in response sion was reported in human pancreatic is- possibility that questions the source of to diabetogenic factors, palmitic acid, or lets by the same group (Krus et al., 2014), C3 in islet samples. To that end, the au- islet amyloid polypeptide, demonstrating as a follow-up, the authors explored the thors demonstrate that C3 is expressed a key cytoprotective role of C3 and autorole of complement C3 in b cell autophagy in human pancreatic islets, since in situ phagy in b cells. Taken together, these studies suggest and survival during diabetes. Indeed, gene hybridization revealed the presence of array data confirmed that C3 is within the C3 mRNA in close proximity to insulin that obesity-induced cytokines drive C3 top 4% genes expressed in human islets. mRNA. Immunofluorescence for C3 in expression in islets. In fact, IL-1b binds Unlike mouse islets, normal rat islets also dispersed human islets and immunopre- to its response element in C3 gene and exhibit modest complement C3 expres- cipitation of pro-C3 and C3 a and b promotes C3 expression (Wilson et al., sion; however, C3 expression greatly chains further confirmed that C3 protein 1990). C3 protein sustains autophagy increased in both diabetic db/db mice synthesis occurs in islets. These exciting and prevents b cell death under diabetoand GK rats as opposed to their healthy findings suggest that C3 may be the genic conditions (Figure 1). However, controls. Furthermore, the authors report elusive stimulant of b cell autophagy dur- these studies do not show whether C3-ATG16L1 interaction is required for 158% increase in C3 expression in type ing obesity. and b cell survival. 2 diabetic donors when compared to Is complement C3 required for b cell autophagy healthy donors and that C3 expression autophagy? Interestingly, exploration for Mapping the interaction of C3 with correlates positively with typical indices interacting partners of C3 revealed auto- ATG16L1 and generating mutants to block for assessment of diabetes and inflamma- phagy protein ATG16L1 as a major interac- C3-ATG16L1 interaction will likely reveal tion—body mass index, HbA1c, and cyto- tor. Since C3 does not have known the answer. The authors show that loss kines IL-1b and TNF-a. Quite interestingly, receptors, the authors confirmed via ELISA of C3 disrupts autophagosome-lysosome Cell Metabolism 29, January 8, 2019 5
Cell Metabolism
Previews fusion without affecting autophagosome biogenesis. This is surprising, since ATG16L1 is required for synthesis of preautophagic structures from the plasma membrane through its interaction with clathrin (Ravikumar et al., 2010). It is therefore possible that ATG16L1 regulates distinct aspects of autophagy regulation by binding to different proteins; in this case, its interaction with C3 regulates autophagosome-lysosome fusion in b cells. Nevertheless, King et al. (2018) identify complement C3 as the ‘‘safe-keeper’’ of autophagy in b cells under diabetogenic conditions—providing an avenue to explore new strategies to prevent autophagy failure and b cell death during obesity and diabetes.
REFERENCES Ebato, C., Uchida, T., Arakawa, M., Komatsu, M., Ueno, T., Komiya, K., Azuma, K., Hirose, T., Tanaka, K., Kominami, E., et al. (2008). Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab. 8, 325–332. Jung, H.S., Chung, K.W., Won Kim, J., Kim, J., Komatsu, M., Tanaka, K., Nguyen, Y.H., Kang, T.M., Yoon, K.H., Kim, J.W., et al. (2008). Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 8, 318–324. King, B.C., Kulak, K., Krus, U., Rosberg, R., Golec, E., Wozniak, K., Gomez, M.F., Zhang, E., O’Connell, D.J., Renstro¨m, E., and Blom, A.M. (2018). Complement component C3 is highly expressed in human pancreatic islets and prevents b cell death via ATG16L1 interaction and autophagy regulation. Cell Metab. 29, this issue, 202–210.
ACKNOWLEDGMENTS This work was supported by National Institutes of Health (NIH) grants R01AG043517, R21AG 056754, P30DK020541, and P01AG031782 and American Diabetes Association grants 1-17-PMF011 and 1-18-IBS-062.
Krus, U., King, B.C., Nagaraj, V., Gandasi, N.R., Sjo¨lander, J., Buda, P., Garcia-Vaz, E., Gomez, M.F., Ottosson-Laakso, E., Storm, P., et al. (2014). The complement inhibitor CD59 regulates insulin secretion by modulating exocytotic events. Cell Metab. 19, 883–890.
Liszewski, M.K., Kolev, M., Le Friec, G., Leung, M., Bertram, P.G., Fara, A.F., Subias, M., Pickering, M.C., Drouet, C., Meri, S., et al. (2013). Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39, 1143–1157. Marsh, B.J., Soden, C., Alarco´n, C., Wicksteed, B.L., Yaekura, K., Costin, A.J., Morgan, G.P., and Rhodes, C.J. (2007). Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine beta-cells. Mol. Endocrinol. 21, 2255–2269. Ravikumar, B., Moreau, K., Jahreiss, L., Puri, C., and Rubinsztein, D.C. (2010). Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat. Cell Biol. 12, 747–757. Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A.M., and Czaja, M.J. (2009). Autophagy regulates lipid metabolism. Nature 458, 1131–1135. Wilson, D.R., Juan, T.S., Wilde, M.D., Fey, G.H., and Darlington, G.J. (1990). A 58-base-pair region of the human C3 gene confers synergistic inducibility by interleukin-1 and interleukin-6. Mol. Cell. Biol. 10, 6181–6191. Yang, L., Li, P., Fu, S., Calay, E.S., and Hotamisligil, G.S. (2010). Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467–478.
A ‘‘Connexin’’ Responsible for the Fatal Attraction of Cancer to Bone David L. Waning,1 Theresa A. Guise,2 and Khalid S. Mohammad2,* 1Penn
State College of Medicine, Department of Cellular and Molecular Physiology and Penn State Cancer Institute, Hershey, PA, USA University School of Medicine, Department of Medicine and IU Simon Cancer Center, Indianapolis, IN, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.12.014 2Indiana
Tumor cell interactions with the bone microenvironment are vital for the establishment and progression of bone metastases. Recently in Cancer Cell, Wang et al. (2018) showed that cells of the osteoblast lineage are critical for the delivery of calcium to tumor cells through gap junctions, pointing toward potential therapies for bone metastases. Bone is a common site for metastases from breast, prostate, lung, and other cancers. The associated morbidity of bone pain, fractures, hypercalcemia, nerve compression, and muscle weakness is devastating, can last for years, and renders the disease incurable. A current therapy directed against the tumor and the bone-resorbing osteoclast improves this morbidity but does not cure the disease. The lack of effective
therapies for bone metastases is partially due to incomplete understanding of the underlying mechanisms that drive the metastatic process. Tumor cells arrive in the bone microenvironment and interact with resident cells, including osteoclasts, osteoblasts, osteocytes, hematopoietic cells, and other stromal cells. Cancer cells stimulate osteoclastic bone resorption, which causes release of growth factors, such
6 Cell Metabolism 29, January 8, 2019 ª 2018 Elsevier Inc.
as transforming growth factor beta (TGFb) and calcium from the mineralized bone matrix. These factors drive tumor growth and a feedforward vicious cycle of continuous bone destruction (Weilbaecher et al., 2011). The role of osteogenic cells (defined as cells of the osteoblast lineage and mesenchymal stem cells) in initiation and progression of bone metastases has become increasingly evident. Osteoblasts
Previews is downstream of the profibrogenic platelet-derived growth factor (PDGF), and loss of fibrosis in the absence of STAT-1 in HSCs could occur due to reduced PDGF-mediated HSC activation (Gandhi, 2017). Some studies in STAT-1deficient mice have found increased fibrosis and proposed that STAT-1 inhibits HSC proliferation, but these were in the CCl4 toxin model rather than a NASH model (Jeong et al., 2006). There may be additional indirect effects due to reduced inflammation and liver injury, with the subsequent reduction in profibrogenic signals from damaged hepatocytes. The recognized role of STAT-3 inhibitors in a range of cancers has resulted in a number of strategies to block STAT-3 activity, including peptides, peptidomimetics, small molecule inhibitors, and knockdown approaches, and a number are in clinical trials (Furqan et al., 2013). There has been much less interest in STAT-1 inhibitors, but the current work suggests that such inhibition may be a strategy for the treatment of NASH.
REFERENCES Abe, M., Yoshida, T., Akiba, J., Ikezono, Y., Wada, F., Masuda, A., Sakaue, T., Tanaka, T., Iwamoto, H., Nakamura, T., et al. (2017). STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. World J. Gastroenterol. 23, 6833–6844. Diehl, A.M., and Day, C. (2017). Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N. Engl. J. Med. 377, 2063–2072. Fatemipour, M., Arabzadeh, S.A.M., Molaei, H., Geramizadeh, B., Dabiri, S., Fatemipour, B., Vahedi, S.M., and Malekpour Afshar, R. (2017). Evaluation of STAT3 rs1053004 single nucleotide polymorphism in patients with chronic hepatitis B and hepatocellular carcinoma. Cell. Mol. Biol. 63, 45–50. Furqan, M., Akinleye, A., Mukhi, N., Mittal, V., Chen, Y., and Liu, D. (2013). STAT inhibitors for cancer therapy. J. Hematol. Oncol. 6, 90. Gandhi, C.R. (2017). Hepatic stellate cell activation and pro-fibrogenic signals. J. Hepatol. 67, 1104–1105. Grohmann, M., Wiede, F., Dodd, G.T., Gurzov, E.N., Ooi, G.J., Butt, T., Rasmiena, A.A., Kaur, S., Gulati, T., Goh, P.K., et al. (2018). Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 175, 1289–1306.e20.
Hong, F., Jaruga, B., Kim, W.H., Radaeva, S., El-Assal, O.N., Tian, Z., Nguyen, V.A., and Gao, B. (2002). Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J. Clin. Invest. 110, 1503–1513. Jeong, W.I., Park, O., Radaeva, S., and Gao, B. (2006). STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity. Hepatology 44, 1441–1451. Kim, W.H., Hong, F., Radaeva, S., Jaruga, B., Fan, S., and Gao, B. (2003). STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G761–G768. Kulik, L., and El-Serag, H.B. (2018). Epidemiology and management of hepatocellular carcinoma. Gastroenterology. Published online October 24, 2018. https://doi.org/10.1053/j.gastro.2018.08.065. Masarone, M., Rosato, V., Dallio, M., Gravina, A.G., Aglitti, A., Loguercio, C., Federico, A., and Persico, M. (2018). Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid. Med. Cell. Longev. 2018, 9547613. Stine, J.G., Wentworth, B.J., Zimmet, A., Rinella, M.E., Loomba, R., Caldwell, S.H., and Argo, C.K. (2018). Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment. Pharmacol. Ther. 48, 696–703.
Complement C3 and Autophagy Keep the b Cell Alive Miriam Toledo1,2 and Rajat Singh1,2,3,4,5,* 1Department
of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA 3Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA 4Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA 5The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY 10461, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.12.010 2Department
Autophagy prevents pancreatic b cell death during obesity, although the mechanism of autophagy activation in the b cell has remained elusive. In this issue of Cell Metabolism, King et al. (2018) show that intracellular complement component C3 interacts with autophagy protein ATG16L1 and protects against b cell death by stimulating autophagy. Autophagy is a conserved ‘‘in-bulk’’ lysosomal quality control pathway that degrades cytoplasmic components with precision and selectivity—aged or damaged organelles are eliminated while intact organelles are spared. Given its ability to degrade both proteins and organelles, the impact of autophagy failure on cell function is significant, and the pancre-
atic b cell is no exception. However, the mechanisms that trigger autophagy in pancreatic b cells have remained elusive. In this work, King et al. (2018 [this issue of Cell Metabolism]) reveal an exciting new link between inflammatory pathways and cytoprotective autophagy in b cells, which could help develop strategies to prevent b cell loss during obesity.
4 Cell Metabolism 29, January 8, 2019 ª 2018 Elsevier Inc.
The evidence highlighting the role of autophagy in b cell function comes from studies showing that compensatory expansion of b cells during obesity requires autophagy, and that absence of autophagy impairs insulin secretion and glucose intolerance (Ebato et al., 2008; Jung et al., 2008). In fact, loss of autophagy revealed tell-tale signs of impaired
Cell Metabolism
Previews quality control, i.e., ‘‘balloonthat C3, and not its cleaved products, like’’ degeneration of b cells, interacts with ATG16L1. During autop62 inclusions, and damaged phagy, ATG16L1 binds to ATG12mitochondria (Ebato et al., ATG5 conjugate to generate a heter2008; Jung et al., 2008). This led otrimeric E3 ligase for light-chain 3 to the question—what triggers b (LC3) lipidation, a key step in autocell autophagy during obesity? phagosome formation. Given this Interestingly, starvation, a wellinformation, the authors tested established stimulus for autowhether C3 is required for autophagy phagy, fails to induce autophagy in insulin-secreting rat INS-1 cells. in b cells in vivo (Ebato et al., Autophagy flux analyses in C32008). Since obesity associates depleted cells (C3 / ) showed a remarkable suppression of autowith increased circulating lipid, phagy and accumulation of p62 aginvestigations have since gregates, which are degraded by focused on establishing a causal autophagy. Autophagy also turns link between free fatty acids over insulin granules via crinophagy (FFAs) and autophagy. While (Marsh et al., 2007), and in keeping FFAs stimulate autophagy in with this notion, C3 / b cells disrat-derived INS-1 b cells in culplayed an accumulation of insulin ture (Ebato et al., 2008), whether that resulted in increased insulin FFAs directly stimulate b cell secretion when C3 / b cells were autophagy in vivo remains unsubjected to glucose stimulation. tested. Furthermore, while Increased insulin secretion is likely obesity and lipid accumulation an early effect of C3 depletion in suppress autophagy in liver cultured b cells, and it is conceivable (Singh et al., 2009; Yang et al., that sustained loss of C3 in mice will 2010), b cell autophagy is gradually dampen insulin secretion remarkably induced in obese Figure 1. Islet-Intrinsic Complement C3 Expression as has been observed in b cell-spemice (Ebato et al., 2008), pointing Regulates Autophagy and Prevents b Cell Death cific autophagy gene Atg7-deficient to yet-unknown b cell-intrinsic Obesity-induced cytokines induce C3 gene expression in islets. Cell-intrinsic C3 protein interacts with autophagy protein ATG16L1 mice (Ebato et al., 2008; Jung et al., factors that stimulate autophagy to drive autophagy that protects b cells from apoptosis under 2008). Importantly, given that autoduring stress. diabetogenic conditions. IAPP, islet amyloid polypeptide. phagy mitigates cellular stress, the Enter complement C3—a authors then tested whether C3 deficomponent of the conserved innate immune system and a key humoral no increases were observed in expres- ciency and autophagy failure sensitizes mediator of inflammation, which has sion of receptors for active products of INS-1 cells to death under diabetogenic recently been shown to exhibit non-ca- C3 cleavage or factors known to regulate conditions. Indeed, C3 / b cells, as well nonical functions in cell survival (Liszewski C3 cleavage, suggesting that C3 may it- as those depleted of Atg7, each showed et al., 2013). Since increased C3 expres- self impact b cell function—an interesting marked increase in apoptosis in response sion was reported in human pancreatic is- possibility that questions the source of to diabetogenic factors, palmitic acid, or lets by the same group (Krus et al., 2014), C3 in islet samples. To that end, the au- islet amyloid polypeptide, demonstrating as a follow-up, the authors explored the thors demonstrate that C3 is expressed a key cytoprotective role of C3 and autorole of complement C3 in b cell autophagy in human pancreatic islets, since in situ phagy in b cells. Taken together, these studies suggest and survival during diabetes. Indeed, gene hybridization revealed the presence of array data confirmed that C3 is within the C3 mRNA in close proximity to insulin that obesity-induced cytokines drive C3 top 4% genes expressed in human islets. mRNA. Immunofluorescence for C3 in expression in islets. In fact, IL-1b binds Unlike mouse islets, normal rat islets also dispersed human islets and immunopre- to its response element in C3 gene and exhibit modest complement C3 expres- cipitation of pro-C3 and C3 a and b promotes C3 expression (Wilson et al., sion; however, C3 expression greatly chains further confirmed that C3 protein 1990). C3 protein sustains autophagy increased in both diabetic db/db mice synthesis occurs in islets. These exciting and prevents b cell death under diabetoand GK rats as opposed to their healthy findings suggest that C3 may be the genic conditions (Figure 1). However, controls. Furthermore, the authors report elusive stimulant of b cell autophagy dur- these studies do not show whether C3-ATG16L1 interaction is required for 158% increase in C3 expression in type ing obesity. and b cell survival. 2 diabetic donors when compared to Is complement C3 required for b cell autophagy healthy donors and that C3 expression autophagy? Interestingly, exploration for Mapping the interaction of C3 with correlates positively with typical indices interacting partners of C3 revealed auto- ATG16L1 and generating mutants to block for assessment of diabetes and inflamma- phagy protein ATG16L1 as a major interac- C3-ATG16L1 interaction will likely reveal tion—body mass index, HbA1c, and cyto- tor. Since C3 does not have known the answer. The authors show that loss kines IL-1b and TNF-a. Quite interestingly, receptors, the authors confirmed via ELISA of C3 disrupts autophagosome-lysosome Cell Metabolism 29, January 8, 2019 5
Cell Metabolism
Previews fusion without affecting autophagosome biogenesis. This is surprising, since ATG16L1 is required for synthesis of preautophagic structures from the plasma membrane through its interaction with clathrin (Ravikumar et al., 2010). It is therefore possible that ATG16L1 regulates distinct aspects of autophagy regulation by binding to different proteins; in this case, its interaction with C3 regulates autophagosome-lysosome fusion in b cells. Nevertheless, King et al. (2018) identify complement C3 as the ‘‘safe-keeper’’ of autophagy in b cells under diabetogenic conditions—providing an avenue to explore new strategies to prevent autophagy failure and b cell death during obesity and diabetes.
REFERENCES Ebato, C., Uchida, T., Arakawa, M., Komatsu, M., Ueno, T., Komiya, K., Azuma, K., Hirose, T., Tanaka, K., Kominami, E., et al. (2008). Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab. 8, 325–332. Jung, H.S., Chung, K.W., Won Kim, J., Kim, J., Komatsu, M., Tanaka, K., Nguyen, Y.H., Kang, T.M., Yoon, K.H., Kim, J.W., et al. (2008). Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 8, 318–324. King, B.C., Kulak, K., Krus, U., Rosberg, R., Golec, E., Wozniak, K., Gomez, M.F., Zhang, E., O’Connell, D.J., Renstro¨m, E., and Blom, A.M. (2018). Complement component C3 is highly expressed in human pancreatic islets and prevents b cell death via ATG16L1 interaction and autophagy regulation. Cell Metab. 29, this issue, 202–210.
ACKNOWLEDGMENTS This work was supported by National Institutes of Health (NIH) grants R01AG043517, R21AG 056754, P30DK020541, and P01AG031782 and American Diabetes Association grants 1-17-PMF011 and 1-18-IBS-062.
Krus, U., King, B.C., Nagaraj, V., Gandasi, N.R., Sjo¨lander, J., Buda, P., Garcia-Vaz, E., Gomez, M.F., Ottosson-Laakso, E., Storm, P., et al. (2014). The complement inhibitor CD59 regulates insulin secretion by modulating exocytotic events. Cell Metab. 19, 883–890.
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A ‘‘Connexin’’ Responsible for the Fatal Attraction of Cancer to Bone David L. Waning,1 Theresa A. Guise,2 and Khalid S. Mohammad2,* 1Penn
State College of Medicine, Department of Cellular and Molecular Physiology and Penn State Cancer Institute, Hershey, PA, USA University School of Medicine, Department of Medicine and IU Simon Cancer Center, Indianapolis, IN, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.12.014 2Indiana
Tumor cell interactions with the bone microenvironment are vital for the establishment and progression of bone metastases. Recently in Cancer Cell, Wang et al. (2018) showed that cells of the osteoblast lineage are critical for the delivery of calcium to tumor cells through gap junctions, pointing toward potential therapies for bone metastases. Bone is a common site for metastases from breast, prostate, lung, and other cancers. The associated morbidity of bone pain, fractures, hypercalcemia, nerve compression, and muscle weakness is devastating, can last for years, and renders the disease incurable. A current therapy directed against the tumor and the bone-resorbing osteoclast improves this morbidity but does not cure the disease. The lack of effective
therapies for bone metastases is partially due to incomplete understanding of the underlying mechanisms that drive the metastatic process. Tumor cells arrive in the bone microenvironment and interact with resident cells, including osteoclasts, osteoblasts, osteocytes, hematopoietic cells, and other stromal cells. Cancer cells stimulate osteoclastic bone resorption, which causes release of growth factors, such
6 Cell Metabolism 29, January 8, 2019 ª 2018 Elsevier Inc.
as transforming growth factor beta (TGFb) and calcium from the mineralized bone matrix. These factors drive tumor growth and a feedforward vicious cycle of continuous bone destruction (Weilbaecher et al., 2011). The role of osteogenic cells (defined as cells of the osteoblast lineage and mesenchymal stem cells) in initiation and progression of bone metastases has become increasingly evident. Osteoblasts