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Cellular traffic cops: the interplay between lipids and proteins regulates vesicular formation, trafficking, and signaling in mammalian cells
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ScienceDirect Cellular traffic cops: the interplay between lipids and proteins regulates vesicular formation, trafficking, and signaling in mammalian cells Amit Kumar1, Deniz Baycin-Hizal2, Yue Zhang1, Michael A Bowen2 and Michael J Betenbaugh1 Protein secretion and vesicular trafficking in mammalian cells rely on several key lipids including sphingolipids, phospholipids, and neutral lipids crucial to protein processing and other intracellular events. Proteins interact with these lipids to alter the shape of lipid bilayer, thereby playing a pivotal role in cellular sorting. Although some efforts have elucidated the role of these components, extensive studies are needed to further decipher the protein–lipid interactions along with the effect of membrane curvature and rafts in sorting of proteins. The regulatory role of proteins in subcellular localization and metabolism of lipids also needs to be described. Recent studies on the role of lipid–protein interactions in modulating membrane shape, signal transduction, and vesicular trafficking are presented in this review. Addresses 1 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA 2 Antibody Discovery and Protein Engineering, MedImmune, Gaithersburg, MD 20878, USA Corresponding author: Betenbaugh, Michael J ([email protected], [email protected])
Current Opinion in Biotechnology 2015, 36:215–221 This review comes from a themed issue on Pathway engineering Edited by Michael J Betenbaugh and William E Bentley For a complete overview see the Issue and the Editorial Available online 2nd November 2015 http://dx.doi.org/10.1016/j.copbio.2015.09.006 0958-1669/# 2015 Elsevier Ltd. All rights reserved.
Introduction Lipid metabolism regulates vesicular transport, signal transduction, and protein secretion through various mechanisms. Carrier vesicles interconnect cellular compartments of eukaryotic cells by budding and fusion. Vesicles bud from a membrane in one compartment and eventually fuse with a different membrane to release their contents into another location in the cell or to the extracellular space. The matrix of cellular membranes for these vesicles is a fluid lipid bilayer containing several lipids differing in polar head groups and lipophilic tails, typically in combination with a variety of structural or signaling proteins. For bidirectional www.sciencedirect.com
and fast vesicular transport, the turnover rates of membrane components play significant roles [1]. Recent work has also highlighted the significant regulatory role played by both lipids and proteins in vesicle trafficking and intracellular vesicle transport. This review will highlight recent studies that examine the importance of lipids and the interactions of proteins and lipids on vesicular formation, trafficking, and signaling, with a focus on mammalian cells.
Effects of various lipids on vesicle processing A number of lipids can play key roles in vesicular trafficking. For example, (1) sphingolipids can alter SNAREs’ (Soluble N-ethylmaleimide sensitive fusion [NSF] attachment protein receptors) ability to mediate membrane fusion, (2) glycerophospholipids regulate vesicle transport, and (3) sorting of glycosylphosphatidylinositol lipid anchors in the endoplasmic reticulum (ER) [2]. Summarized in Table 1 are some recent studies and the relevant lipids and lipoproteins involved in vesicular trafficking. In addition to the effects of lipids on vesicular transport, studies have shown that cholesterol is essential for efficient ER to Golgi transport of membrane proteins [3,4]. However, it has also been reported that an excessive accumulation of cholesterol in the ER can have inhibitory effects on vesicular trafficking and protein secretion [5]. Likewise, exposure of saturated and unsaturated fatty acids including phosphatidylcholine (PC) can contribute to lipotoxic ER stress in some cell types. Alterations in lipids can also cause induction of both terminal ER stress and lipo-apoptosis and suggest the need for an optimal lipid composition [6]. In this way, lipids play roles both in vesicular transport as well as ER homeostasis in a healthy mammalian cell. Recently, lipidomics has become increasingly utilized as a tool to investigate the roles of lipids in cardiovascular and neurological disorders [7]. As a result, mass spectral based lipidomics and comparative lipidomics techniques aided by isotope labelling approaches have been established [8– 10]. These advanced analytical methods will become increasingly important for evaluating the roles of lipids and proteins in cellular functions including and beyond vesicular trafficking.
The role of protein–lipid interactions on membrane curvature, protein sorting, and traffic regulation In this section, we discuss recent studies in elucidating the significance of membrane shape in producing centers Current Opinion in Biotechnology 2015, 36:215–221
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Table 1 Summary of recent studies on lipids involved in protein sorting and vesicular trafficking Function
Recent study
Sphingolipids
Protein sorting and signal transduction
Lysophospholipids
Cell signaling and trafficking
Lipoproteins
Protein trafficking modulation
Glycerophospholipids
Lipids transport between organelles
& Identified structural factors of lipid-raft association [11] & Validated significant role of lipids in membrane domains formation during protein sorting [11] & Identified role of sphingolipids as crucial signal mediators [12] & Shed new light on role of sphingosine 1-phosphate signaling in vascular and lymphatic systems, immune system, nervous system, and oncogenesis [13] & Identified secreted lipoproteins to be part of type I and type VI protein secretion systems in Bacteroides fragilis [14] & Experimentally identified and validated the role of ABCA1 transporter mediated efflux of cholesterol and glycerophosphocholine in generating lipid-rafts like protein complexes [15] & Utilized glycerophospholipids to study sterol transport from the ER to the mitochondria in yeast [16] & Reported on specific protein-lipid interactions for transport of phosphatidylserine from ER to endosomes [17]
Lipid
for vesicular trafficking and the interplay between membrane lipids and curvature-generating or curvature-sensing proteins. Membrane curvature and vesicle formation in mammalian cells play important role in vesicular trafficking and include a component of protein sorting on the transmembrane (TM) domain which is dependent on complex and dynamic physicochemical behavior of the TM domain [18,19]. Membrane curvature is driven by a number of different cellular events and structures, such as molecular crowding by proteins and caveolae (a subset of lipid rafts characterized by small cavities in the plasma membrane containing a complex set of proteins such as caveolins and cavins [20]) and protein scaffolding mechanisms as depicted in Figure 1. Two prominent ways by which large membrane curvatures are generated are hydrophobic mismatch as a result of protein crowding (Figure 1a) and scaffolding mechanisms (Figure 1b) [21]. Hydrophobic mismatch results from proteins which have large extra-membrane components diffusing in the membrane, inducing molecular crowding in order to lower the accessible membrane surface area. It is a result of mismatch in length of the hydrophobic part of a protein in transmembrane domain and the bilayer membrane thickness. The mismatch in length can result in an energy penalty which is minimized by clustering of proteins near the membrane leading to curved membrane domains (as shown in Figure 1a). The mismatched proteins at the curved membranes are then exported out of the ER [22,23]. Sorting of proteins with a TM segment at the extreme C-terminus can be affected by hydrophobic mismatch at the ER-Golgi complex interface, which can regulate the molecular crowding at the TM. Moreover, hydrophobic mismatch induced membrane curvature can influence the protein sorting by altering the transmembrane domain size and the dynamics of its formation [24]. Specifically, it can also lead to Current Opinion in Biotechnology 2015, 36:215–221
segregation of homologous SNARE proteins, which are responsible for fusion of secretory vesicles to the plasma membrane [25], into separate lipid-dependent membrane domains [23]. Furthermore, it was recently discovered that the SNARE proteins can induce vesicle formation with as much as a 40% decrease in the surface area accessible to membrane cargo proteins [26]. Intrinsically curved and disordered proteins in mammalian cells, such as Epsin1 and AP180, can also result in membrane curvature [27]. Owing to large hydrodynamic radii of such proteins with intrinsically disordered domains, the molecular crowding is significantly increased, which subsequently increases the membrane curvature [27]. In addition, scaffolding mechanisms, as shown in Figure 1b, can produce positive or negative curvatures in the membrane by virtue of attachment of the hydrophilic portion of a protein domain or protein scaffold. Recently, a computational study demonstrated the effect of interaction between anisotropic proteins on membrane curvature and found a significant role in inducing scaffold crowding at the membrane [28]. Shown in Figure 1c are caveolae participating in membrane bending, which is primarily induced by the interaction of the protein — caveolin — with the lipid packing in membrane bilayer. Recently, it was demonstrated that caveolin-1 adopts an intramembrane U-shaped turn, thereby leading to invaginations in the membrane and the subsequent curvature [29]. Additional membrane proteins can also alter the lipids compositions and influence membrane shape, which can ultimately influence vesicle formation, protein trafficking, and other cellular events. For example, phospholipid www.sciencedirect.com
Protein–lipid interactions regulate vesicular traffic Kumar et al. 217
Figure 1
Protein crowding by hydrophobic mismatch
(a)
(b)
Scaffolding - Positive
(c) Scaffolding - Negative
Caveolae Current Opinion in Biotechnology
Mechanisms of how proteins can alter membrane curvature — (a) protein crowding near the membrane caused by hydrophobic crowding, (b) scaffolding in which proteins attached to the plasma membrane can cause positive or negative membrane curvature, and (c) crowding by selfassembling caveolae, which are major regulators of membrane tension and can produce membrane curvature.
flippases mediate the transfer of phosphatidylserine (PS) between the luminal and the cytoplasmic leaflet of membrane bilayers, inducing curvature and eventual membrane deformation necessary for vesicle scission [30]. In the future, coupling genome wide studies of proteins participating in lipid interactions and membrane curvature with lipid biophysical and chemical compositions may be helpful in increasing our understanding of the roles that these proteins can play in altering vesicle conformation and function.
Membrane proteins and lipids interaction modulates signaling and trafficking In this section, recent findings on the role of membrane lipids on recruiting peripheral or extrinsic proteins, which are proteins temporarily attached to integral membrane proteins in lipid bilayer, for modulation of cell signaling pathways and vesicular trafficking are described. Glycosylceramides or sphingolipids, particularly sphingomyelin in association with cholesterol, help define ‘microdomains’ of the membrane that influence receptor signaling and the functions of important transport proteins [31,32]. For example, sphingolipid-cholesterol microdomains influence signal recognition by GPI-anchored proteins and by palmitoylated TM proteins [33]. Phospholipids such as PtdIns3P (phosphatidylinositol 3-phosphate) control www.sciencedirect.com
various vital cellular functions via recruiting specific protein effectors to membranes in a reversible manner and also stimulate regulated exocytosis [34]. In turn enzymes such as PI3K-C2a (Phosphatidylinositol 3-kinase class II aisoform) regulate lipid functions by binding to PtDIns3P on a membrane and regulating formation of PtDIns3P. PI3K-C2a is also required for optimal translocation of vesicles containing GLUT4 glucose transporters from intracellular locations to the plasma membrane in response to insulin stimulation [35]. Likewise, this PI3K-II isoform has been implicated in the exocytosis of insulin granules from pancreatic b cells and neurosecretory granules from neuroendocrine cells [36]. In association with members of the sorting nexin (SNX) family proteins, some PtdIns3P effectors mediate sorting of membrane proteins to vacuoles or lysosomes and sorting of proteins to the plasma membrane and the trans-Golgi network [37]. For instance, the phosphatidylinositol-3-phosphate (PI3P) lipid binding domain of SNX3 can negatively regulate phagocytosis in dendritic cells by modulating the binding of essential phagocytosis pathway proteins, such as EEA1 (early endosome antigen 1), to the phagosomal membranes [38]. In some cases, membrane curvature can affect intracellular signaling pathways. In the presence of curved membranes, phosphoinositides influences actin polymerization by Current Opinion in Biotechnology 2015, 36:215–221
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engaging membrane binding proteins [39]. Recently, it was discovered that the main difference between the canonical H-Ras, N-Ras, and K-Ras GTPases isoforms is that membrane curvature allows isoforms to partition between liquid-ordered and liquid-disordered phases. Ras superfamily proteins and other lipid-anchored proteins were found to be exclusively associated with highly curved membrane domains, such as caveolae invaginations [40]. More studies on elucidating the functions and dynamics of lipids such as phospholipids and sphingolipids and their interplay with the peripheral proteins will aid understanding and control of processes such as autophagy and regulated exocytosis.
Sphingolipids play major role in membrane trafficking This section highlights the significance of the sphingolipids in regulating dynamic composition of lipid rafts, protein interaction networks, membrane stability and vesicular traffic. Sphingolipids contribute to the formation of membrane domains such as rafts and caveolae, which are enriched in growth factor receptors, cholesterol, transporters, and other proteins, especially those with a glycosylphosphatidylinositiol (GPI)-lipid anchor [41], and function as major modulators of vesicular traffic and cell signal transduction [42,43]. Variable lipid and protein composition in lipid rafts provides an additional sorting paradigm that controls transport, protein–protein interactions, and signal transduction. The physical properties of rafts play a key role in these interactions and under external stimulus the sphingolipids composition in lipid
rafts may be altered, thereby altering the membrane morphology [44]. It is proposed that the segregation and sorting of GPIanchored secretory proteins (or GPI-APs) might be influenced by the saturation of the lipid moiety and subsequent cluster into the lipid rafts [45]. Moreover, it was found that an increase in the GPI-AP clustering level by cargo receptors that bind glycosphingolipids, for example, galectin-9, favors sorting in mammalian cells [46]. In another study, sphingomyelin phosphodiesterase (SMase), which is involved in metabolism of sphingolipids, can alter vesicular trafficking by its ability to reduce sphingomyelin and hence increase the formation of vesicles in erythrocytes by more than 20-fold-, which alters the membrane fragility [47]. Lipid rafts can also play a crucial role in both survival and proliferation signal transduction pathways, including the PI3K/Akt signaling, cancer development and progression, and apoptosis [48,49]. Shown in Figure 2 are a collection of key vesicular transport events facilitated by lipid rafts as well as caveolae, which itself are a specialized variant of lipid rafts. Alteration in lipid raft composition and its association with diseases such as Huntington’s disease needs to be further studied for discovery of novel pharmaceuticals.
Membrane phospholipids biomarkers regulate secondary messengers In previous sections, we have discussed role of lipid– protein interactions in modulating membrane geometry and membrane microdomains. In this section, we discuss
Figure 2
Signal molecule
Cholesterol Vesicle fusion (SNARE, Galectins)
Sphingolipid
Phospholipid
Growth factor receptor
Lipid rafts
G-coupled protein receptor
Lipid rafts
TGN
Lipid raft mediated endocytosis
AKT
Golgi
Transformation ER
Caveolae mediated endocytosis
Current Opinion in Biotechnology
Lipid rafts are involved in various protein trafficking events. Lipid rafts contain G-coupled protein receptors and growth receptors which can be used for endocytosis and signal transduction pathways. The left hand expanded view shows the essential constituents of lipid rafts — cholesterol, sphingolipids, and phospholipids. Current Opinion in Biotechnology 2015, 36:215–221
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Protein–lipid interactions regulate vesicular traffic Kumar et al. 219
the role of interactions between proteins and membrane phospholipids in regulating vesicular trafficking through signaling messengers and recent studies describing them as potential biomarkers for diseases such as cancer. Membrane phospholipids are acted upon by a host of enzymes such as phospholipases, lipid kinases and phosphatases to generate signaling lipids. Similarly, glycerophospholipids can modulate cell signaling by altering the levels of secondary messengers. For example, the turnover of phosphatidylinositol (PI) has been implicated in modulating cell signaling by altering the levels of important secondary messengers such as diacylglycerol (DG) and inositol-1,4,5-triphosphate [50]. Phospholipase D (PLDs) are involved in membrane trafficking events, including budding of vesicles from the Golgi apparatus and the trans-Golgi network as well as the regulation of the formation of clathrin coated vesicles associated with the Golgi apparatus and the morphological maintenance of Golgi apparatus and lysosomes in duct cells from the parotid gland [51]. PLD1, PLD2, and PLD3 have all been implicated in Alzheimer’s disease [52], and PLD3 has been found in secretory granules in an insulin-producing pancreatic b-cell line and in lysosomes of HeLa cells, suggesting that PLD3 protein may traffic through endosomal pathways [52]. Phosphatidic acid (PA), the hydrolysis product of PLD, is an intracellular lipid messenger, recruiting clathrin-coats and other necessary components for vesicle formation, and has been implicated in a wide range of physiological disorders including inflammation, diabetes, and oncogenesis [53]. Vesicle budding, receptor internalization, and recycling is enhanced by activation of PLD, which leads to accumulation of PA. PA can be metabolized to lysophosphatidic acid (LPA), which can bind to Raf-1 kinase, which functions in the ERK1/2 pathway as a MAP kinase (MAP3K) and part of the Ras subfamily of GTPases [54]. Recently, a study using high-resolution spatial mapping demonstrated that different Ras nanoclusters, which exhibit different lipid compositions, are involved in isoformbased lipid sorting [55]. Active PLD enhances lymphoma cell metastasis while inactive PLD2 inhibits metastasis. Studies have shown that inhibition of PLD2 (but not PLD1) inhibits nuclear ERK activity in a variety of cancer cells, causing a reduction in ERK-targeted gene expression. Thus targeting PLD2 could suppress ERK-mediated cancer cell growth factor signaling [56]. Future work needs to focus on understanding the interaction between PLD and other signaling networks and implications on vesicle formation, membrane processing, and in various human diseases. www.sciencedirect.com
Conclusions The interplay between lipids and proteins in mammalian and other eukaryotic cells can alter the chemical compositions and physical properties of membrane lipids, thereby regulating transport vesicle formation and trafficking. The spontaneous segregation of lipids and proteins into different compositions and phases, resulting in their sorting, plays key roles in determining their cellular destinations and signaling events. More work is needed to uncover the linkage between various diseases and role of changes in lipid composition and lipid–protein interactions. Future work will likely include a greater application of ‘omics analysis of different cell types, tissues, and organisms in order to unravel the various roles of lipids and lipid–protein complexes in a range of cellular events. For example, researchers can now investigate in greater detail the gene products involved in formation and degradation of various lipid classes and combine these profiles to lipidomics analyses in order to elucidate the functions of different cellular enzymes and their impact on lipid composition, vesicular formation, trafficking, and cell signaling. Further studies will be essential to tease out the selective contributions of lipids, proteins, and their combinations in order to establish the key players involved in membrane geometry and their association with vesicle formation, budding, sorting, signaling, secretion and human diseases.
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ScienceDirect Cellular traffic cops: the interplay between lipids and proteins regulates vesicular formation, trafficking, and signaling in mammalian cells Amit Kumar1, Deniz Baycin-Hizal2, Yue Zhang1, Michael A Bowen2 and Michael J Betenbaugh1 Protein secretion and vesicular trafficking in mammalian cells rely on several key lipids including sphingolipids, phospholipids, and neutral lipids crucial to protein processing and other intracellular events. Proteins interact with these lipids to alter the shape of lipid bilayer, thereby playing a pivotal role in cellular sorting. Although some efforts have elucidated the role of these components, extensive studies are needed to further decipher the protein–lipid interactions along with the effect of membrane curvature and rafts in sorting of proteins. The regulatory role of proteins in subcellular localization and metabolism of lipids also needs to be described. Recent studies on the role of lipid–protein interactions in modulating membrane shape, signal transduction, and vesicular trafficking are presented in this review. Addresses 1 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA 2 Antibody Discovery and Protein Engineering, MedImmune, Gaithersburg, MD 20878, USA Corresponding author: Betenbaugh, Michael J ([email protected], [email protected])
Current Opinion in Biotechnology 2015, 36:215–221 This review comes from a themed issue on Pathway engineering Edited by Michael J Betenbaugh and William E Bentley For a complete overview see the Issue and the Editorial Available online 2nd November 2015 http://dx.doi.org/10.1016/j.copbio.2015.09.006 0958-1669/# 2015 Elsevier Ltd. All rights reserved.
Introduction Lipid metabolism regulates vesicular transport, signal transduction, and protein secretion through various mechanisms. Carrier vesicles interconnect cellular compartments of eukaryotic cells by budding and fusion. Vesicles bud from a membrane in one compartment and eventually fuse with a different membrane to release their contents into another location in the cell or to the extracellular space. The matrix of cellular membranes for these vesicles is a fluid lipid bilayer containing several lipids differing in polar head groups and lipophilic tails, typically in combination with a variety of structural or signaling proteins. For bidirectional www.sciencedirect.com
and fast vesicular transport, the turnover rates of membrane components play significant roles [1]. Recent work has also highlighted the significant regulatory role played by both lipids and proteins in vesicle trafficking and intracellular vesicle transport. This review will highlight recent studies that examine the importance of lipids and the interactions of proteins and lipids on vesicular formation, trafficking, and signaling, with a focus on mammalian cells.
Effects of various lipids on vesicle processing A number of lipids can play key roles in vesicular trafficking. For example, (1) sphingolipids can alter SNAREs’ (Soluble N-ethylmaleimide sensitive fusion [NSF] attachment protein receptors) ability to mediate membrane fusion, (2) glycerophospholipids regulate vesicle transport, and (3) sorting of glycosylphosphatidylinositol lipid anchors in the endoplasmic reticulum (ER) [2]. Summarized in Table 1 are some recent studies and the relevant lipids and lipoproteins involved in vesicular trafficking. In addition to the effects of lipids on vesicular transport, studies have shown that cholesterol is essential for efficient ER to Golgi transport of membrane proteins [3,4]. However, it has also been reported that an excessive accumulation of cholesterol in the ER can have inhibitory effects on vesicular trafficking and protein secretion [5]. Likewise, exposure of saturated and unsaturated fatty acids including phosphatidylcholine (PC) can contribute to lipotoxic ER stress in some cell types. Alterations in lipids can also cause induction of both terminal ER stress and lipo-apoptosis and suggest the need for an optimal lipid composition [6]. In this way, lipids play roles both in vesicular transport as well as ER homeostasis in a healthy mammalian cell. Recently, lipidomics has become increasingly utilized as a tool to investigate the roles of lipids in cardiovascular and neurological disorders [7]. As a result, mass spectral based lipidomics and comparative lipidomics techniques aided by isotope labelling approaches have been established [8– 10]. These advanced analytical methods will become increasingly important for evaluating the roles of lipids and proteins in cellular functions including and beyond vesicular trafficking.
The role of protein–lipid interactions on membrane curvature, protein sorting, and traffic regulation In this section, we discuss recent studies in elucidating the significance of membrane shape in producing centers Current Opinion in Biotechnology 2015, 36:215–221
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Table 1 Summary of recent studies on lipids involved in protein sorting and vesicular trafficking Function
Recent study
Sphingolipids
Protein sorting and signal transduction
Lysophospholipids
Cell signaling and trafficking
Lipoproteins
Protein trafficking modulation
Glycerophospholipids
Lipids transport between organelles
& Identified structural factors of lipid-raft association [11] & Validated significant role of lipids in membrane domains formation during protein sorting [11] & Identified role of sphingolipids as crucial signal mediators [12] & Shed new light on role of sphingosine 1-phosphate signaling in vascular and lymphatic systems, immune system, nervous system, and oncogenesis [13] & Identified secreted lipoproteins to be part of type I and type VI protein secretion systems in Bacteroides fragilis [14] & Experimentally identified and validated the role of ABCA1 transporter mediated efflux of cholesterol and glycerophosphocholine in generating lipid-rafts like protein complexes [15] & Utilized glycerophospholipids to study sterol transport from the ER to the mitochondria in yeast [16] & Reported on specific protein-lipid interactions for transport of phosphatidylserine from ER to endosomes [17]
Lipid
for vesicular trafficking and the interplay between membrane lipids and curvature-generating or curvature-sensing proteins. Membrane curvature and vesicle formation in mammalian cells play important role in vesicular trafficking and include a component of protein sorting on the transmembrane (TM) domain which is dependent on complex and dynamic physicochemical behavior of the TM domain [18,19]. Membrane curvature is driven by a number of different cellular events and structures, such as molecular crowding by proteins and caveolae (a subset of lipid rafts characterized by small cavities in the plasma membrane containing a complex set of proteins such as caveolins and cavins [20]) and protein scaffolding mechanisms as depicted in Figure 1. Two prominent ways by which large membrane curvatures are generated are hydrophobic mismatch as a result of protein crowding (Figure 1a) and scaffolding mechanisms (Figure 1b) [21]. Hydrophobic mismatch results from proteins which have large extra-membrane components diffusing in the membrane, inducing molecular crowding in order to lower the accessible membrane surface area. It is a result of mismatch in length of the hydrophobic part of a protein in transmembrane domain and the bilayer membrane thickness. The mismatch in length can result in an energy penalty which is minimized by clustering of proteins near the membrane leading to curved membrane domains (as shown in Figure 1a). The mismatched proteins at the curved membranes are then exported out of the ER [22,23]. Sorting of proteins with a TM segment at the extreme C-terminus can be affected by hydrophobic mismatch at the ER-Golgi complex interface, which can regulate the molecular crowding at the TM. Moreover, hydrophobic mismatch induced membrane curvature can influence the protein sorting by altering the transmembrane domain size and the dynamics of its formation [24]. Specifically, it can also lead to Current Opinion in Biotechnology 2015, 36:215–221
segregation of homologous SNARE proteins, which are responsible for fusion of secretory vesicles to the plasma membrane [25], into separate lipid-dependent membrane domains [23]. Furthermore, it was recently discovered that the SNARE proteins can induce vesicle formation with as much as a 40% decrease in the surface area accessible to membrane cargo proteins [26]. Intrinsically curved and disordered proteins in mammalian cells, such as Epsin1 and AP180, can also result in membrane curvature [27]. Owing to large hydrodynamic radii of such proteins with intrinsically disordered domains, the molecular crowding is significantly increased, which subsequently increases the membrane curvature [27]. In addition, scaffolding mechanisms, as shown in Figure 1b, can produce positive or negative curvatures in the membrane by virtue of attachment of the hydrophilic portion of a protein domain or protein scaffold. Recently, a computational study demonstrated the effect of interaction between anisotropic proteins on membrane curvature and found a significant role in inducing scaffold crowding at the membrane [28]. Shown in Figure 1c are caveolae participating in membrane bending, which is primarily induced by the interaction of the protein — caveolin — with the lipid packing in membrane bilayer. Recently, it was demonstrated that caveolin-1 adopts an intramembrane U-shaped turn, thereby leading to invaginations in the membrane and the subsequent curvature [29]. Additional membrane proteins can also alter the lipids compositions and influence membrane shape, which can ultimately influence vesicle formation, protein trafficking, and other cellular events. For example, phospholipid www.sciencedirect.com
Protein–lipid interactions regulate vesicular traffic Kumar et al. 217
Figure 1
Protein crowding by hydrophobic mismatch
(a)
(b)
Scaffolding - Positive
(c) Scaffolding - Negative
Caveolae Current Opinion in Biotechnology
Mechanisms of how proteins can alter membrane curvature — (a) protein crowding near the membrane caused by hydrophobic crowding, (b) scaffolding in which proteins attached to the plasma membrane can cause positive or negative membrane curvature, and (c) crowding by selfassembling caveolae, which are major regulators of membrane tension and can produce membrane curvature.
flippases mediate the transfer of phosphatidylserine (PS) between the luminal and the cytoplasmic leaflet of membrane bilayers, inducing curvature and eventual membrane deformation necessary for vesicle scission [30]. In the future, coupling genome wide studies of proteins participating in lipid interactions and membrane curvature with lipid biophysical and chemical compositions may be helpful in increasing our understanding of the roles that these proteins can play in altering vesicle conformation and function.
Membrane proteins and lipids interaction modulates signaling and trafficking In this section, recent findings on the role of membrane lipids on recruiting peripheral or extrinsic proteins, which are proteins temporarily attached to integral membrane proteins in lipid bilayer, for modulation of cell signaling pathways and vesicular trafficking are described. Glycosylceramides or sphingolipids, particularly sphingomyelin in association with cholesterol, help define ‘microdomains’ of the membrane that influence receptor signaling and the functions of important transport proteins [31,32]. For example, sphingolipid-cholesterol microdomains influence signal recognition by GPI-anchored proteins and by palmitoylated TM proteins [33]. Phospholipids such as PtdIns3P (phosphatidylinositol 3-phosphate) control www.sciencedirect.com
various vital cellular functions via recruiting specific protein effectors to membranes in a reversible manner and also stimulate regulated exocytosis [34]. In turn enzymes such as PI3K-C2a (Phosphatidylinositol 3-kinase class II aisoform) regulate lipid functions by binding to PtDIns3P on a membrane and regulating formation of PtDIns3P. PI3K-C2a is also required for optimal translocation of vesicles containing GLUT4 glucose transporters from intracellular locations to the plasma membrane in response to insulin stimulation [35]. Likewise, this PI3K-II isoform has been implicated in the exocytosis of insulin granules from pancreatic b cells and neurosecretory granules from neuroendocrine cells [36]. In association with members of the sorting nexin (SNX) family proteins, some PtdIns3P effectors mediate sorting of membrane proteins to vacuoles or lysosomes and sorting of proteins to the plasma membrane and the trans-Golgi network [37]. For instance, the phosphatidylinositol-3-phosphate (PI3P) lipid binding domain of SNX3 can negatively regulate phagocytosis in dendritic cells by modulating the binding of essential phagocytosis pathway proteins, such as EEA1 (early endosome antigen 1), to the phagosomal membranes [38]. In some cases, membrane curvature can affect intracellular signaling pathways. In the presence of curved membranes, phosphoinositides influences actin polymerization by Current Opinion in Biotechnology 2015, 36:215–221
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engaging membrane binding proteins [39]. Recently, it was discovered that the main difference between the canonical H-Ras, N-Ras, and K-Ras GTPases isoforms is that membrane curvature allows isoforms to partition between liquid-ordered and liquid-disordered phases. Ras superfamily proteins and other lipid-anchored proteins were found to be exclusively associated with highly curved membrane domains, such as caveolae invaginations [40]. More studies on elucidating the functions and dynamics of lipids such as phospholipids and sphingolipids and their interplay with the peripheral proteins will aid understanding and control of processes such as autophagy and regulated exocytosis.
Sphingolipids play major role in membrane trafficking This section highlights the significance of the sphingolipids in regulating dynamic composition of lipid rafts, protein interaction networks, membrane stability and vesicular traffic. Sphingolipids contribute to the formation of membrane domains such as rafts and caveolae, which are enriched in growth factor receptors, cholesterol, transporters, and other proteins, especially those with a glycosylphosphatidylinositiol (GPI)-lipid anchor [41], and function as major modulators of vesicular traffic and cell signal transduction [42,43]. Variable lipid and protein composition in lipid rafts provides an additional sorting paradigm that controls transport, protein–protein interactions, and signal transduction. The physical properties of rafts play a key role in these interactions and under external stimulus the sphingolipids composition in lipid
rafts may be altered, thereby altering the membrane morphology [44]. It is proposed that the segregation and sorting of GPIanchored secretory proteins (or GPI-APs) might be influenced by the saturation of the lipid moiety and subsequent cluster into the lipid rafts [45]. Moreover, it was found that an increase in the GPI-AP clustering level by cargo receptors that bind glycosphingolipids, for example, galectin-9, favors sorting in mammalian cells [46]. In another study, sphingomyelin phosphodiesterase (SMase), which is involved in metabolism of sphingolipids, can alter vesicular trafficking by its ability to reduce sphingomyelin and hence increase the formation of vesicles in erythrocytes by more than 20-fold-, which alters the membrane fragility [47]. Lipid rafts can also play a crucial role in both survival and proliferation signal transduction pathways, including the PI3K/Akt signaling, cancer development and progression, and apoptosis [48,49]. Shown in Figure 2 are a collection of key vesicular transport events facilitated by lipid rafts as well as caveolae, which itself are a specialized variant of lipid rafts. Alteration in lipid raft composition and its association with diseases such as Huntington’s disease needs to be further studied for discovery of novel pharmaceuticals.
Membrane phospholipids biomarkers regulate secondary messengers In previous sections, we have discussed role of lipid– protein interactions in modulating membrane geometry and membrane microdomains. In this section, we discuss
Figure 2
Signal molecule
Cholesterol Vesicle fusion (SNARE, Galectins)
Sphingolipid
Phospholipid
Growth factor receptor
Lipid rafts
G-coupled protein receptor
Lipid rafts
TGN
Lipid raft mediated endocytosis
AKT
Golgi
Transformation ER
Caveolae mediated endocytosis
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Lipid rafts are involved in various protein trafficking events. Lipid rafts contain G-coupled protein receptors and growth receptors which can be used for endocytosis and signal transduction pathways. The left hand expanded view shows the essential constituents of lipid rafts — cholesterol, sphingolipids, and phospholipids. Current Opinion in Biotechnology 2015, 36:215–221
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Protein–lipid interactions regulate vesicular traffic Kumar et al. 219
the role of interactions between proteins and membrane phospholipids in regulating vesicular trafficking through signaling messengers and recent studies describing them as potential biomarkers for diseases such as cancer. Membrane phospholipids are acted upon by a host of enzymes such as phospholipases, lipid kinases and phosphatases to generate signaling lipids. Similarly, glycerophospholipids can modulate cell signaling by altering the levels of secondary messengers. For example, the turnover of phosphatidylinositol (PI) has been implicated in modulating cell signaling by altering the levels of important secondary messengers such as diacylglycerol (DG) and inositol-1,4,5-triphosphate [50]. Phospholipase D (PLDs) are involved in membrane trafficking events, including budding of vesicles from the Golgi apparatus and the trans-Golgi network as well as the regulation of the formation of clathrin coated vesicles associated with the Golgi apparatus and the morphological maintenance of Golgi apparatus and lysosomes in duct cells from the parotid gland [51]. PLD1, PLD2, and PLD3 have all been implicated in Alzheimer’s disease [52], and PLD3 has been found in secretory granules in an insulin-producing pancreatic b-cell line and in lysosomes of HeLa cells, suggesting that PLD3 protein may traffic through endosomal pathways [52]. Phosphatidic acid (PA), the hydrolysis product of PLD, is an intracellular lipid messenger, recruiting clathrin-coats and other necessary components for vesicle formation, and has been implicated in a wide range of physiological disorders including inflammation, diabetes, and oncogenesis [53]. Vesicle budding, receptor internalization, and recycling is enhanced by activation of PLD, which leads to accumulation of PA. PA can be metabolized to lysophosphatidic acid (LPA), which can bind to Raf-1 kinase, which functions in the ERK1/2 pathway as a MAP kinase (MAP3K) and part of the Ras subfamily of GTPases [54]. Recently, a study using high-resolution spatial mapping demonstrated that different Ras nanoclusters, which exhibit different lipid compositions, are involved in isoformbased lipid sorting [55]. Active PLD enhances lymphoma cell metastasis while inactive PLD2 inhibits metastasis. Studies have shown that inhibition of PLD2 (but not PLD1) inhibits nuclear ERK activity in a variety of cancer cells, causing a reduction in ERK-targeted gene expression. Thus targeting PLD2 could suppress ERK-mediated cancer cell growth factor signaling [56]. Future work needs to focus on understanding the interaction between PLD and other signaling networks and implications on vesicle formation, membrane processing, and in various human diseases. www.sciencedirect.com
Conclusions The interplay between lipids and proteins in mammalian and other eukaryotic cells can alter the chemical compositions and physical properties of membrane lipids, thereby regulating transport vesicle formation and trafficking. The spontaneous segregation of lipids and proteins into different compositions and phases, resulting in their sorting, plays key roles in determining their cellular destinations and signaling events. More work is needed to uncover the linkage between various diseases and role of changes in lipid composition and lipid–protein interactions. Future work will likely include a greater application of ‘omics analysis of different cell types, tissues, and organisms in order to unravel the various roles of lipids and lipid–protein complexes in a range of cellular events. For example, researchers can now investigate in greater detail the gene products involved in formation and degradation of various lipid classes and combine these profiles to lipidomics analyses in order to elucidate the functions of different cellular enzymes and their impact on lipid composition, vesicular formation, trafficking, and cell signaling. Further studies will be essential to tease out the selective contributions of lipids, proteins, and their combinations in order to establish the key players involved in membrane geometry and their association with vesicle formation, budding, sorting, signaling, secretion and human diseases.
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