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BBA - Molecular and Cell Biology of Lipids (v.1821, #8)

Editorial Board (pp. i).

Lipids and vesicular transport by Brugger Britta Brügger; Vytas A. Bankaitis (pp. 1039-1039).

Vesicle-mediated ER export of proteins and lipids by Amanda D. Gillon; Catherine F. Latham; Elizabeth A. Miller (pp. 1040-1049).

In eukaryotic cells, the endoplasmic reticulum (ER) is a major site of synthesis of both lipids and proteins, many of which must be transported to other organelles. The COPII coat—comprising Sar1, Sec23/24, Sec13/31—generates transport vesicles that mediate the bulk of protein/lipid export from the ER. The coat exhibits remarkable flexibility in its ability to specifically select and accommodate a large number of cargoes with diverse properties. In this review, we discuss the fundamentals of COPII vesicle production and describe recent advances that further our understanding of just how flexible COPII cargo recruitment and vesicle formation may be. Large or bulky cargo molecules (e.g. collagen rods and lipoprotein particles) exceed the canonical size for COPII vesicles and seem to rely on the additional action of recently identified accessory molecules. Although the bulk of the research has focused on the fate of protein cargo, the mechanisms and regulation of lipid transport are equally critical to cellular survival. From their site of synthesis in the ER, phospholipids, sphingolipids and sterols exit the ER, either accompanying cargo in vesicles or directly across the cytoplasm shielded by lipid-transfer proteins. Finally, we highlight the current challenges to the field in addressing the physiological regulation of COPII vesicle production and the molecular details of how diverse cargoes, both proteins and lipids, are accommodated. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► Transport of lipids and proteins from the ER is a highly regulated process. ► Protein exit from the ER occurs via signal-mediate export and bulk flow. ► The COPII machinery can adapt to export large or bulky cargoes. ► ER export of lipids occurs via both vesicular and non-vesicular mechanisms.

Keywords: Abbreviations; CLSD; cranio-lenticulo-sutural dysplasia; GEF; guanine nucleotide exchange factor; GAP; GTPase-activating protein; ERES; ER exit sites; ERt, ER; transitional; VSV-Gm; vesicular stomatitis virus glycoprotein; VTCs; vesicular tubular clusters; ERGIC; ER-Golgi intermediate compartment; SNARE; soluble N-ethylmaleimide attachment receptor; GPI-APs; glycophosphosphatidylinositol-anchored proteins; TANGO1; transport and golgi organization 1; cTAGE5; c; utaneous T-cell lymphoma-associated antigen 5; PRD; proline-rich domain; UPR; unfolded protein response; FA; fatty acid; VLDL; very low-density lipoprotein; FABP; fatty acid binding protein; apo; apolipoprotein; PCTV; prechylomicron transport vesicle; VAMP7; vesicle-associated membrane protein 7; L-FABP; liver FABP; VTVs; VLDL transport vesicles; MCS; membrane contact sites; LTPs; lipid-transfer proteins; StAR; steroidogenic acute regulatoryCOPII; Cargo export; Collagen; Lipid; Vesicle; Endoplasmic reticulum

GPI-anchor remodeling: Potential functions of GPI-anchors in intracellular trafficking and membrane dynamics by Morihisa Fujita; Taroh Kinoshita (pp. 1050-1058).

Glycosylphosphatidylinositol (GPI) anchoring of proteins is a conserved post-translational modification in eukaryotes. GPI is synthesized and transferred to proteins in the endoplasmic reticulum. GPI-anchored proteins are then transported from the endoplasmic reticulum to the plasma membrane through the Golgi apparatus. GPI-anchor functions as a sorting signal for transport of GPI-anchored proteins in the secretory and endocytic pathways. After GPI attachment to proteins, the structure of the GPI-anchor is remodeled, which regulates the trafficking and localization of GPI-anchored proteins. Recently, genes required for GPI remodeling were identified in yeast and mammalian cells. Here, we describe the structural remodeling and function of GPI-anchors, and discuss how GPI-anchors regulate protein sorting, trafficking, and dynamics. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► GPI-anchor functions as a sorting signal for transport of GPI-anchored proteins. ► During delivery to the plasma membranes, the GPI moiety is remodeled. ► The remodeling confers characteristic properties on GPI-anchored proteins. ► We discuss how GPI-anchors regulate protein sorting, trafficking, and dynamics.

Keywords: Abbreviations; ACE; angiotensin-converting enzyme; CLIC; clathrin-independent carrier; COPII; coat protein complex II; DRM; detergent-resistant membrane; ER; endoplasmic reticulum; ERES; ER-exit sites; EtNP; ethanolamine-phosphate; GalNAc; N; -acetylgalactosamine; GEEC; GPI-APs enriched early endosomal compartment; GlcN; glucosamine; GPI; glycosylphosphatidylinositol; GPI-AP; GPI-anchored protein; Lo; liquid order; Man; mannose; MBOAT; membrane-bound; O; -acyltransferase; PE; phosphatidylethanolamine; PI; phosphatidylinositol; PNH; paroxysmal nocturnal hemoglobinuria; STALL; stimulation-induced temporary arrest of lateral diffusion; tER; transitional ER; TGN; trans-Golgi network; VacA; vacuolating cytotoxinEndoplasmic reticulum; Glycosylphosphatidylinositol; Golgi apparatus; Lipid raft; Sorting; Trafficking

Lipid-dependent protein sorting at the trans-Golgi network by Michal A. Surma; Christian Klose; Kai Simons (pp. 1059-1067).

In eukaryotic cells, the trans-Golgi network serves as a sorting station for post-Golgi traffic. In addition to coat- and adaptor-mediated mechanisms, studies in mammalian epithelial cells and yeast have provided evidence for lipid-dependent protein sorting as a major delivery mechanism for cargo sorting to the cell surface. The mechanism for lipid-mediated sorting is the generation of raft platforms of sphingolipids, sterols and specific sets of cargo proteins by phase segregation in the TGN. Here, we review the evidence for such lipid-raft-based sorting at the TGN, as well as their involvement in the formation of TGN-to-PM transport carriers. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► This review highlights lipid involvement in membrane sorting at the TGN. ► Data support the role of lipid rafts in cargo segregation and carrier formation. ► Clustering of lipid rafts is a prerequisite for these processes. ► Clustering and carrier formation is supported by auxiliary proteinous factors. ► Fine tuning of lipid composition is likely to further regulate these processes.

Keywords: Lipid raft; Trans-Golgi network; Sorting; Cargo; Golgi apparatus; Secretory pathway

Phospholipid flippases: Building asymmetric membranes and transport vesicles by Tessy T. Sebastian; Ryan D. Baldridge; Peng Xu; Todd R. Graham (pp. 1068-1077).

Phospholipid flippases in the type IV P-type ATPase family (P4-ATPases) are essential components of the Golgi, plasma membrane and endosomal system that play critical roles in membrane biogenesis. These pumps flip phospholipid across the bilayer to create an asymmetric membrane structure with substrate phospholipids, such as phosphatidylserine and phosphatidylethanolamine, enriched within the cytosolic leaflet. The P4-ATPases also help form transport vesicles that bud from Golgi and endosomal membranes, thereby impacting the sorting and localization of many different proteins in the secretory and endocytic pathways. At the organismal level, P4-ATPase deficiencies are linked to liver disease, obesity, diabetes, hearing loss, neurological deficits, immune deficiency and reduced fertility. Here, we review the biochemical, cellular and physiological functions of P4-ATPases, with an emphasis on their roles in vesicle-mediated protein transport. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► Evidence that type IV P-type ATPases (P4-ATPases) are phospholipid flippases. ► Phospholipid flippases create membrane phospholipid asymmetry. ► Phospholipid flippases play critical roles in vesicular transport. ► P4-ATPases are linked to many disease states. ► Mechanisms for regulating flippase activity are being uncovered.

Keywords: Phospholipid flippase; Vesicular transport; Flippase; P4-ATPase; Drs2; Cdc50

Regulation of the Golgi complex by phospholipid remodeling enzymes by Kevin D. Ha; Benjamin A. Clarke; William J. Brown (pp. 1078-1088).

The mammalian Golgi complex is a highly dynamic organelle consisting of stacks of flattened cisternae with associated coated vesicles and membrane tubules that contribute to cargo import and export, intra-cisternal trafficking, and overall Golgi architecture. At the morphological level, all of these structures are continuously remodeled to carry out these trafficking functions. Recent advances have shown that continual phospholipid remodeling by phospholipase A (PLA) and lysophospholipid acyltransferase (LPAT) enzymes, which deacylate and reacylate Golgi phospholipids, respectively, contributes to this morphological remodeling. Here we review the identification and characterization of four cytoplasmic PLA enzymes and one integral membrane LPAT that participate in the dynamic functional organization of the Golgi complex, and how some of these enzymes are integrated to determine the relative abundance of COPI vesicle and membrane tubule formation.This article is part of a Special Issue entitled Lipids and Vesicular Transport.► PLA₂ and LPAT membrane remodeling influences mammalian Golgi structure and function. ► PAFAHIb, cPLA_2α, PLA2G6/iPLA₂-β, and iPLA₁γ localize to the Golgi complex. ► PAFAHIb, cPLA_2α, and PLA2G6/iPLA₂-β induce Golgi membrane tubule formation. ► The transmembrane LPAT AGPAT3/LPAAT3 regulates Golgi structure and function. ► AGPAT3/LPAAT3 and cPLA₂α influence COPI vesicle and membrane tubule formation.

Keywords: Abbreviations; AA; Arachidonic acid; ACAT; acyl-CoA cholesterol acyltransferase; AGPAT; 1-acylglycerol-3-phosphate acyltransferase; Arf; ADP-ribosylating factor; BARS; BFA-inhibited, ADP-ribosylated substrate; BFA; Brefeldin A; CPT1; Choline-phosphotransferase; DAG; Diacylglycerol; DAGK; Diacylglycerol kinase; ER; Endoplasmic reticulum; ERES; ER exit site; ERGIC; ER-Golgi-intermediate complex; GEF; Guanine nucleotide exchange factor; GUV; Giant unilamellar vesicle; L; _o; Liquid ordered; L; _d; Liquid disordered; LPA; Lysophosphatidic acid; LPAAT; Lysophosphatidic acid acyltransferase; LPAT; Lysophospholipid acyltransferase; LPC; Lysophosphatidylcholine; LPE; Lysophosphatidylethanolamine; LPL; Lysophospholipid; MAFP; Methyl arachidonyl fluorophosphonate; MBOAT; Membrane bound O-acyltransferase; MT; Microtubule; MTOC; Microtubule organizing center; PA; Phosphatidic acid; PACOCF3; palmitoyl trifluoromethylketone; PAFAH; Platelet activating factor acetylhydrolase; PC; Phosphatidylcholine; PIP; Phosphoinositide phosphate; PLA; Phospholipase A; PLAAp; PLA; ₂; activating protein peptide; PLD; Phospholipase D; SM; Sphingomyelin; SMS; Sphingomyelin synthase; SPH; Sphingomyelin; TGN; trans; -Golgi networkGolgi complex; Lands cycle; Cytoplasmic PLA; ₂; Lysophospholipid acyltransferase; COPI coated vesicle; Membrane tubule

Connecting vesicular transport with lipid synthesis: FAPP2 by Giovanni D'Angelo; Laura Rita Rega; Maria Antonietta De Matteis (pp. 1089-1095).

Next to the protein-based machineries composed of small G-proteins, coat complexes, SNAREs and tethering factors, the lipid-based machineries are emerging as important players in membrane trafficking. As a component of these machineries, lipid transfer proteins have recently attracted the attention of cell biologists for their involvement in trafficking along different segments of the secretory pathway. Among these, the four-phosphate adaptor protein 2 (FAPP2) was discovered as a protein that localizes dynamically with the trans-Golgi network and regulates the transport of proteins from the Golgi complex to the cell surface. Later studies have highlighted a role for FAPP2 as lipid transfer protein involved in glycosphingolipid metabolism at the Golgi complex. Here we discuss the available evidence on the function of FAPP2 in both membrane trafficking and lipid metabolism and propose a mechanism of action of FAPP2 that integrates its activities in membrane trafficking and in lipid transfer. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► FAPP2 contains a PtdIns4P (and ARF1) binding PH domain and a GLTP (Glycolipid Transfer Protein) domain. ► The FAPP2-PH domain targets the protein to the trans-Golgi network and has membrane bending activity. ► Via the GLTP domain FAPP2 transfers glucosylceramide and fosters complex glycolipid synthesis at the Golgi complex. ► FAPP2 controls TGN-to-plasma membrane vesicular trafficking by assisting the formation of post-Golgi carriers. ► The lipid-transfer activity of FAPP2 is required for its role in membrane trafficking.

Keywords: Lipid transfer protein; FAPP2; Golgi complex; Glycosphingolipid; Transport carrier

Integration of non-vesicular and vesicular transport processes at the Golgi complex by the PKD–CERT network by Monilola A. Olayioye; Angelika Hausser (pp. 1096-1103).

Non-vesicular transport of ceramide from endoplasmic reticulum to Golgi membranes is essential for cellular lipid homeostasis. Protein kinase D (PKD) is a serine–threonine kinase that controls vesicle fission at Golgi membranes. Here we highlight the intimate connections between non-vesicular and vesicular transport at the level of the Golgi complex, and suggest that PKD and its substrate CERT, the ceramide transfer protein, play central roles in coordinating these processes by fine-tuning the local membrane lipid composition to maintain Golgi secretory function. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► PKD phosphorylates PI4KIIIβ, CERT and OSBP, all of which are involved in lipid metabolism or trafficking. ► This molecular network coordinates non-vesicular and vesicular trafficking ensuring proper Golgi function. ► CERT-mediated non-vesicular ceramide transfer occurs at ER–Golgi membrane contact sites. ► Deregulated CERT is involved in human pathologies and its function is exploited by human pathogens.

Keywords: Lipid transfer protein; Serine phosphorylation; Trans; -Golgi network; Membrane contact site; Secretion

Phosphoinositides and vesicular membrane traffic by Peter Mayinger (pp. 1104-1113).

Phosphoinositide lipids were initially discovered as precursors for specific second messengers involved in signal transduction, but have now taken the center stage in controlling many essential processes at virtually every cellular membrane. In particular, phosphoinositides play a critical role in regulating membrane dynamics and vesicular transport. The unique distribution of certain phosphoinositides at specific intracellular membranes makes these molecules uniquely suited to direct organelle-specific trafficking reactions. In this regulatory role, phosphoinositides cooperate specifically with small GTPases from the Arf and Rab families. This review will summarize recent progress in the study of phosphoinositides in membrane trafficking and organellar organization and highlight the particular relevance of these signaling pathways in disease. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► Phosphoinositide lipids are critical regulators of membrane traffic. ► Important roles in exocytosis, endocytosis, endosomal traffic and Golgi function. ► Additional roles in autophagy and organellar dynamics. ► Relationship to human disease is discussed.

Keywords: Phosphoinositide; Membrane traffic; Lipid kinase; Lipid phosphatase; Golgi; Endocytosis

Coupling exo- and endocytosis: An essential role for PIP₂ at the synapse by Marta Koch; Matthew Holt (pp. 1114-1132).

Chemical synapses are specialist points of contact between two neurons, where information transfer takes place. Communication occurs through the release of neurotransmitter substances from small synaptic vesicles in the presynaptic terminal, which fuse with the presynaptic plasma membrane in response to neuronal stimulation. However, as neurons in the central nervous system typically only possess ~200 vesicles, high levels of release would quickly lead to a depletion in the number of vesicles, as well as leading to an increase in the area of the presynaptic plasma membrane (and possible misalignment with postsynaptic structures). Hence, synaptic vesicle fusion is tightly coupled to a local recycling of synaptic vesicles. For a long time, however, the exact molecular mechanisms coupling fusion and subsequent recycling remained unclear. Recent work now indicates a unique role for the plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP₂), acting together with the vesicular protein synaptotagmin, in coupling these two processes. In this work, we review the evidence for such a mechanism and discuss both the possible advantages and disadvantages for vesicle recycling (and hence signal transduction) in the nervous system. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► PIP₂ at the synapse: structure, synthesis and localization. ► PIP₂ and synaptotagmin: implications for synaptic vesicle exocytosis. ► PIP₂ and synaptotagmin: roles in synaptic vesicle endocytosis. ► Coupling of exo- and endocytosis. ► Future directions for lipid research at the synapse.

Keywords: Abbreviations; AP; Adaptor protein; Arf; ADP-ribosylation factor; CALM; clathrin assembly lymphoid myeloid leukemia protein; CAPS; Calcium activated protein for secretion; Cdk; Cyclin-dependent kinase; DAG; Diacylglycerol; EMS; Ethyl methanesulfonate; FCHo1/2; F-BAR domain-containing Fer/Cip4 homology domain-only proteins 1 and 2; GFP; Green fluorescent protein; GST; glutathione S-transferase; HIP; Huntingtin interacting protein; IP; ₃; Inositol trisphosphate; MARCM; Mosaic analysis with a repressible cell marker; NMJ; Neuromuscular junction; PH; Pleckstrin homology; PIP; ₂; Phosphatidylinositol 4,5-bisphosphate; PKC; Protein kinase C; PLC; Phospholipase C; PLD; Phospholipase D; PS; Phosphatidylserine; PX; Phox; RIM; Rab3 interacting molecule; SCAMP; Secretory carrier membrane protein; SHD; Stonin homology domain; SNARE; Soluble NSF attachment protein receptor; VAMP; Vesicle associated membrane protein; μHD; mu-homology domainPhosphatidylinositol 4,5-bisphosphate; Synaptic vesicle; Exocytosis; Endocytosis; Synaptotagmin

Lipids in autophagy: Constituents, signaling molecules and cargo with relevance to disease by Knaevelsrud Helene Knævelsrud; Anne Simonsen (pp. 1133-1145).

The balance between protein and lipid biosynthesis and their eventual degradation is a critical component of cellular health. Autophagy, the catabolic process by which cytoplasmic material becomes degraded in lysosomes, can be induced by various physiological stimuli to maintain cellular homeostasis. Autophagy was for a long time considered a non-selective bulk process, but recent data have shown that unwanted components such as aberrant protein aggregates, dysfunctional organelles and invading pathogens can be selectively eliminated by autophagy. Recently, also intracellular lipid droplets were described as specific autophagic cargo, indicating that autophagy plays a role in lipid metabolism and storage (Singh et al., 2009 ). Moreover, over the past several years, it has become increasingly evident that lipids and lipid-modifying enzymes play important roles in the autophagy process itself, both at the level of regulation of autophagy and as membrane constituents required for formation of autophagic vesicles. In this review, we will discuss the interplay between lipids and autophagy, as well as the role of lipid-binding proteins in autophagy. We also comment on the possible implications of this mutual interaction in the context of disease. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► The intracellular lysosomal degradation pathway autophagy depends on lipids at multiple levels. ► Specific lipid species ensure important properties of autophagic membranes. ► Lipid-binding, lipid-modifying and lipidated proteins are central to the autophagic pathway. ► Autophagy is regulated by upstream lipid signaling. ► Autophagy plays an important role in lipid metabolism in health and disease.

Keywords: Abbreviations; Alfy; autophagy-linked FYVE protein; Atg; autophagy-related; BAR; Bin/Amphiphysin/Rvs-homology; BATS; Barkor/Atg14(L) autophagosome targeting sequence; CL; cardiolipin; CMA; chaperone-mediated autophagy; COPI; coat protein complex I; Cvt; cytoplasm to vacuole targeting; DAG; diacylglycerol; DGK; diacylglycerol kinase; EM; electron microscopy; ER; endoplasmic reticulum; ESCRT; endosomal sorting complex required for transport; HDL; high density lipoproteins; LAMP-2A; lysosome-associated membrane protein type-2A; LC3; MAP1 light chain 3; LD; lipid droplet; LDL; low density lipoproteins; LIR; LC3-interacting region; MEF; mouse embryonic fibroblast; mTOR; mammalian Target of Rapamycin; mTORC1; mTOR complex 1; MVB; multivesicular body; PA; phosphatidic acid; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PI; phosphatidylinositol; PI3K; phosphatidylinositol 3-kinase; PI3P; phospatidylinositol-3-phosphate; PS; phosphatidylserine; S1P; sphingosine-1-phosphate; SK1; sphingosine kinase 1; SPP1; sphingosine-1-phosphate phosphohydrolase; TG; triglyceride; 3-MA; 3-methyladenine; ULK; unc-51-like kinase; UPR; unfolded protein response; UVRAG; ultraviolet irradiation resistance-associated geneAutophagy; Lipophagy; Lipid droplet; PI3P; PE; PA

Cell polarity in myelinating glia: From membrane flow to diffusion barriers by Mikael Simons; Nicolas Snaidero; Shweta Aggarwal (pp. 1146-1153).

Myelin-forming glia are highly polarized cells that synthesize as an extension of their plasma membrane, a multilayered myelin membrane sheath, with a unique protein and lipid composition. In most cells polarity is established by the polarized exocytosis of membrane vesicles to the distinct plasma membrane domains. Since myelin is composed of a stack of tightly packed membrane layers that do not leave sufficient space for the vesicular trafficking, we hypothesize that myelin does not use polarized exocytosis as a primary mechanism, but rather depends on lateral transport of membrane components in the plasma membrane. We suggest a model in which vesicle-mediated transport is confined to the cytoplasmic channels, from where transport to the compacted areas occurs by lateral flow of cargo within the plasma membrane. A diffusion barrier that is formed by MBP and the two adjacent cytoplasmic leaflets of the myelin bilayers acts a molecular sieve and regulates the flow of the components. Finally, we highlight potential mechanism that may contribute to the assembly of specific lipids within myelin. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► Polarization enables the functional specialization of membrane domains in myelin. ► Lateral membrane flow might be a trafficking mechanism in myelin. ► A diffusion barrier that is formed by MBP regulates membrane flow. ► The self-organizing potential of lipids may contribute to the assembly of myelin.

Keywords: Myelin; Oligodendrocyte; Neuron; Polarity

Lipid signaling in Drosophila photoreceptors by Padinjat Raghu; Shweta Yadav; Naresh Babu Naidu Mallampati (pp. 1154-1165).

Drosophila photoreceptors are sensory neurons whose primary function is the transduction of photons into an electrical signal for forward transmission to the brain. Photoreceptors are polarized cells whose apical domain is organized into finger like projections of plasma membrane, microvilli that contain the molecular machinery required for sensory transduction. The development of this apical domain requires intense polarized membrane transport during development and it is maintained by post developmental membrane turnover. Sensory transduction in these cells involves a high rate of G-protein coupled phosphatidylinositol 4,5 bisphosphate [PI(4,5)P₂] hydrolysis ending with the activation of ion channels that are members of the TRP superfamily. Defects in this lipid-signaling cascade often result in retinal degeneration, which is a consequence of the loss of apical membrane homeostasis. In this review we discuss the various membrane transport challenges of photoreceptors and their regulation by ongoing lipid signaling cascades in these cells. This article is part of a Special Issue entitled Lipids and Vesicular Transport.► Photoreceptors are polarized cells with an apical domain specialized to detect light. ► G-protein coupled PI(4,5)P2 hydrolysis is central to sensory transduction. ► Regulated membrane turnover is critical for the normal physiology of these cells. ► Retinal degeneration results from aberrant apical domain homeostasis.

Keywords: Drosophila; Photoreceptor; Sphingolipid; Lipid signaling; Vesicular transport; PI(4,5)P; ₂

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BBA - Molecular and Cell Biology of Lipids (v.1821, #8)