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• W3163858333 abstract "Cholesterol represents the most abundant single lipid in mammalian cells. How its asymmetric distribution between subcellular membranes is achieved and maintained attracts considerable interest. One of the challenges is that cholesterol rarely is transported alone, but rather is coupled with heterotypic transport and metabolism of other lipids, in particular phosphoinositides, phosphatidylserine, and sphingolipids. This perspective summarizes the major exo- and endocytic cholesterol transport routes and how lipid transfer proteins at membrane contacts and membrane transport intersect along these routes. It discusses the co-transport of cholesterol with other lipids in mammalian cells and reviews emerging evidence related to the physiological relevance of this process. Cholesterol represents the most abundant single lipid in mammalian cells. How its asymmetric distribution between subcellular membranes is achieved and maintained attracts considerable interest. One of the challenges is that cholesterol rarely is transported alone, but rather is coupled with heterotypic transport and metabolism of other lipids, in particular phosphoinositides, phosphatidylserine, and sphingolipids. This perspective summarizes the major exo- and endocytic cholesterol transport routes and how lipid transfer proteins at membrane contacts and membrane transport intersect along these routes. It discusses the co-transport of cholesterol with other lipids in mammalian cells and reviews emerging evidence related to the physiological relevance of this process. Cholesterol is an essential component of mammalian cell membranes. All nucleated cells are capable of synthesizing it de novo from the central two-carbon metabolic precursor acetate that is processed to the unique 27-carbon, four-ring structure via a complex series of enzyme reactions. In addition, animal-based food products provide a source of exogenous cholesterol, which after entero-hepatic processing reaches peripheral cells via circulating low-density lipoprotein (LDL) particles. In the receiving cells, receptor-mediated endocytosis of LDL and hydrolysis in acidic compartments transiently enriches late endosomes and lysosomes (LE/Ly) with exogenous cholesterol to be redistributed to other subcellular membranes. Within cells, the distribution of cholesterol is markedly uneven, being highly enriched in the plasma membrane (PM), where it constitutes roughly 40 mol% of all lipids, but low in the endoplasmic reticulum (ER), where it only represents less than 5 mol% of lipids (Ikonen, 2008Ikonen E. Cellular cholesterol trafficking and compartmentalization.Nat. Rev. Mol. Cell Biol. 2008; 9: 125-138Crossref PubMed Scopus (948) Google Scholar; Mesmin and Maxfield, 2009Mesmin B. Maxfield F.R. Intracellular sterol dynamics. Biochim. Biophys. Acta - Mol.Cell Biol. Lipids. 2009; 1791: 636-645Crossref PubMed Scopus (194) Google Scholar) (Figure 1). This is critical for the ER cholesterol-sensing SREBP/SCAP (sterol regulatory element binding protein/SREBP cleavage activating protein) machinery. Membrane trafficking routes communicating with the PM, such as trans-Golgi network (TGN) and recycling endosomal compartments, are cholesterol enriched, and there is a decreasing level of cholesterol content toward the cis-Golgi. Because most of the cholesterol synthesizing enzymes localize to the ER, efficient export mechanisms for ER cholesterol and retention mechanisms for PM cholesterol must be in place. Cholesterol harbors a small polar head group (a single hydroxyl moiety at carbon-3) and is therefore intercalated in the phospholipid bilayer and moves readily between leaflets with an estimated sub-second timescale (Steck and Lange, 2018Steck T.L. Lange Y. Transverse distribution of plasma membrane bilayer cholesterol: Picking sides.Traffic. 2018; 19: 750-760Crossref PubMed Scopus (63) Google Scholar). Cholesterol can be lifted from the bilayer to the aqueous, cytosolic environment with the help of lipid transfer proteins (LTPs) whose hydrophobic cavity shields the lipid from water and can catalyze lipid transfer between organelles. Such transfer processes are often concentrated at membrane contact sites (MCSs) (Figure 2), i.e., regions where membranes are tethered at a close (~10 nm or more) distance (for a recent review, see Prinz et al., 2020Prinz W.A. Toulmay A. Balla T. The functional universe of membrane contact sites.Nat. Rev. Mol. Cell Biol. 2020; 21: 7-24Crossref PubMed Scopus (152) Google Scholar). The dynamic nature of such contacts is emerging as an important principle for metabolic rewiring (Bohnert, 2020Bohnert M. Tether Me, Tether Me Not-Dynamic Organelle Contact Sites in Metabolic Rewiring.Dev. Cell. 2020; 54: 212-225Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). It is also becoming increasingly evident that inter-organelle cholesterol transport can no longer be considered in isolation: cholesterol transfer is often coupled to and geared by the transport and metabolism of other lipids, in particular phosphoinositides (PIPs), phosphatidylserine (PS), and sphingolipids. Keeping these inter-dependencies in mind, the present review aims to provide a brief account of the major exo-and endocytic cholesterol transport routes and how LTPs at membrane contacts and membrane trafficking intersect along these routes. Early studies indicated that efficient export of cholesterol from the ER mostly relies on non-vesicular trafficking (Heino et al., 2000Heino S. Lusa S. Somerharju P. Ehnholm C. Olkkonen V.M. Ikonen E. Dissecting the role of the golgi complex and lipid rafts in biosynthetic transport of cholesterol to the cell surface.Proc. Natl. Acad. Sci. USA. 2000; 97: 8375-8380Crossref PubMed Scopus (206) Google Scholar; Urbani and Simoni, 1990Urbani L. Simoni R.D. Cholesterol and vesicular stomatitis virus G protein take separate routes from the endoplasmic reticulum to the plasma membrane.J. Biol. Chem. 1990; 265: 1919-1923Abstract Full Text PDF PubMed Google Scholar) and identified a protein with an oxysterol-binding domain, OSBP, bridging between the Golgi and ER membranes (Ridgway et al., 1992Ridgway N.D. Dawson P.A. Ho Y.K. Brown M.S. Goldstein J.L. Translocation of oxysterol binding protein to Golgi apparatus triggered by ligand binding.J. Cell Biol. 1992; 116: 307-319Crossref PubMed Scopus (236) Google Scholar; Wyles et al., 2002Wyles J.P. McMaster C.R. Ridgway N.D. Vesicle-associated membrane protein-associated protein-A (VAP-A) interacts with the oxysterol-binding protein to modify export from the endoplasmic reticulum.J. Biol. Chem. 2002; 277: 29908-29918Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). Further work revealed that the yeast OSBP homolog Osh4p can exchange sterols for phosphatidylinositol 4-phosphate (PI4P) between membranes (de Saint-Jean et al., 2011de Saint-Jean M. Delfosse V. Douguet D. Chicanne G. Payrastre B. Bourguet W. Antonny B. Drin G. Osh4p exchanges sterols for phosphatidylinositol 4-phosphate between lipid bilayers.J. Cell Biol. 2011; 195: 965-978Crossref PubMed Scopus (271) Google Scholar) and is in fact 10 times more efficient as a lipid exchanger than as a plain transporter (Moser von Filseck et al., 2015Moser von Filseck J. Vanni S. Mesmin B. Antonny B. Drin G. A phosphatidylinositol-4-phosphate powered exchange mechanism to create a lipid gradient between membranes.Nat. Commun. 2015; 6: 6671Crossref PubMed Scopus (129) Google Scholar). However, some of the Osh4p biology cannot easily be reconciled with this counter-current model of lipid transport (Georgiev et al., 2011Georgiev A.G. Sullivan D.P. Kersting M.C. Dittman J.S. Beh C.T. Menon A.K. Osh proteins regulate membrane sterol organization but are not required for sterol movement between the ER and PM.Traffic. 2011; 12: 1341-1355Crossref PubMed Scopus (95) Google Scholar; Quon et al., 2018Quon E. Sere Y.Y. Chauhan N. Johansen J. Sullivan D.P. Dittman J.S. Rice W.J. Chan R.B. Di Paolo G. Beh C.T. Menon A.K. Endoplasmic reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation.PLoS Biol. 2018; 16: e2003864Crossref PubMed Scopus (74) Google Scholar). Importantly, PI(4)P is enriched in the Golgi and PM (Di Paolo and De Camilli, 2006Di Paolo G. De Camilli P. Phosphoinositides in cell regulation and membrane dynamics.Nature. 2006; 443: 651-657Crossref PubMed Scopus (2020) Google Scholar) but absent in the ER due to the activity of the ER-localized phosphatase Sac1 that dephosphorylates PI(4)P to PI (Foti et al., 2001Foti M. Audhya A. Emr S.D. Sac1 lipid phosphatase and Stt4 phosphatidylinositol 4-kinase regulate a pool of phosphatidylinositol 4-phosphate that functions in the control of the actin cytoskeleton and vacuole morphology.Mol. Biol. Cell. 2001; 12: 2396-2411Crossref PubMed Scopus (182) Google Scholar). Thus, Osh4p can generate a sterol gradient between ER and Golgi membranes by exporting sterol from the ER to the Golgi and transferring PI(4)P to the opposite direction in repeated exchange cycles. Despite being a one-by-one transfer, this process could be efficient enough to account for up to 60% of the sterol delivery that yeast needs in order to double its PM area during asymmetric cell division (Sullivan et al., 2006Sullivan D.P. Ohvo-Rekilä H. Baumann N.A. Beh C.T. Menon A.K. Sterol trafficking between the endoplasmic reticulum and plasma membrane in yeast.Biochem. Soc. Trans. 2006; 34: 356-358Crossref PubMed Scopus (73) Google Scholar). Remarkably, a similar sterol/PI(4) counter-exchange was found to be carried out by OSBP for cholesterol delivery at ER-trans-Golgi contact sites in mammalian cells (Mesmin et al., 2013Mesmin B. Bigay J. Moser von Filseck J. Lacas-Gervais S. Drin G. Antonny B. A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP.Cell. 2013; 155: 830-843Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar) (Figure 2B, Panel 1). The domain architecture of OSBP supports a mechanism by which the protein connects to the ER through its FFAT motif binding to the ER VAP-A protein, and to the TGN via its PH domain that binds to the TGN via dual interaction with PI(4)P and the small GTPase Arf1, transferring cholesterol between these juxtaposed membranes via the OSBP-related domain (ORD) (Levine, 2004Levine T. Short-range intracellular trafficking of small molecules across endoplasmic reticulum junctions.Trends Cell Biol. 2004; 14: 483-490Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). Upon acute chemical inhibition of OSBP, sterol accumulates in the ER and lipid droplets (LDs) at the expense of the TGN (Mesmin et al., 2017Mesmin B. Bigay J. Polidori J. Jamecna D. Lacas-Gervais S. Antonny B. Sterol transfer, PI4P consumption, and control of membrane lipid order by endogenous OSBP.EMBO J. 2017; 36: 3156-3174Crossref PubMed Scopus (99) Google Scholar). Considering the low levels of PI(4)P (roughly 1% of total phospholipids) compared to sterol, an efficient phosphorylation-dephosphorylation cycle of PI(4)P is needed to energize cholesterol delivery against its concentration gradient. Curiously, loss of Sac1 has a minimal impact on monophosphorylated PIPs (Charman et al., 2017Charman M. Goto A. Ridgway N.D. Oxysterol-binding protein recruitment and activity at the endoplasmic reticulum-Golgi interface are independent of Sac1.Traffic. 2017; 18: 519-529Crossref PubMed Scopus (9) Google Scholar), but this may be due to compensatory effects. These findings prompt the next question, i.e., how cholesterol gets onward from the TGN to reach the PM. Interestingly, lipid transfer at ER-Golgi membrane contacts is proposed to promote the biogenesis of TGN-derived carrier vesicles, called CARTS (carriers of the trans-Golgi network to the cell surface), that ferry selective cargoes to the PM through organization of cholesterol- and sphingomyelin (SM)-enriched nanodomains at the TGN (Wakana et al., 2015Wakana Y. Kotake R. Oyama N. Murate M. Kobayashi T. Arasaki K. Inoue H. Tagaya M. CARTS biogenesis requires VAP-lipid transfer protein complexes functioning at the endoplasmic reticulum-Golgi interface.Mol. Biol. Cell. 2015; 26: 4686-4699Crossref PubMed Scopus (34) Google Scholar). Recent results showed that in cholesterol-rich conditions, the ER cholesterol sensor SCAP interacts with Sac1 and promotes the formation of TGN-PM carriers depending on ER cholesterol (Wakana et al., 2021Wakana Y. Hayashi K. Nemoto T. Watanabe C. Taoka M. Angulo-Capel J. Garcia-Parajo M.F. Kumata H. Umemura T. Inoue H. et al.The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER-Golgi membrane contact sites.J. Cell Biol. 2021; 220: e202002150Crossref PubMed Scopus (10) Google Scholar). Whether CARTS represent major carriers for cholesterol delivery from the TGN to the PM remains to be addressed. PI(4)P exchange between membranes and Sac1-dependent PI(4)P dephosphorylation are not only involved in ER cholesterol export but also drive other lipid transport steps, such as the transfer of PS from the ER, its site of synthesis, to the PM where it is enriched in the inner leaflet (Figure 2B, Panel 2). This transfer is mediated by ORP5- and ORP8-mediated counter-transport of PS and PI(4)P (Chung et al., 2015Chung J. Torta F. Masai K. Lucast L. Czapla H. Tanner L.B. Narayanaswamy P. Wenk M.R. Nakatsu F. De Camilli P. INTRACELLULAR TRANSPORT. PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER-plasma membrane contacts.Science. 2015; 349: 428-432Crossref PubMed Scopus (339) Google Scholar). The dynamic recruitment of ORP5/8 to the PM depends on PI(4)P and PI(4,5)P2 (Ghai et al., 2017Ghai R. Du X. Wang H. Dong J. Ferguson C. Brown A.J. Parton R.G. Wu J.W. Yang H. ORP5 and ORP8 bind phosphatidylinositol-4, 5-biphosphate (PtdIns(4,5)P 2) and regulate its level at the plasma membrane.Nat. Commun. 2017; 8: 757Crossref PubMed Scopus (106) Google Scholar), with ORP8 being recruited when PI(4,5)P2 is increased (Sohn et al., 2018Sohn M. Korzeniowski M. Zewe J.P. Wills R.C. Hammond G.R.V. Humpolickova J. Vrzal L. Chalupska D. Veverka V. Fairn G.D. et al.PI(4,5)P2 controls plasma membrane PI4P and PS levels via ORP5/8 recruitment to ER-PM contact sites.J. Cell Biol. 2018; 217: 1797-1813Crossref PubMed Scopus (93) Google Scholar). This provides a mechanism to exquisitely regulate PM PI(4)P, PI(4,5)P2, and PS levels. With high PM PI(4,5)P2, ORP8 and ORP5 are recruited to supply PS and remove PI(4)P, limiting PI(4,5)P2 synthesis from PI(4)P. At low PI(4,5)P2 levels, only ORP5 docks and transfers PS to the PM, until PM PI(4)P is exhausted. Why the PM delivery of PS is relevant for cholesterol transport is discussed in later sections of this perspective. Increasing evidence indicates that LTPs also deliver cholesterol from the ER toward endo-lysosomal compartments via MCSs. This may help to support the formation of intraluminal vesicles in late endosomes under low cholesterol levels, as shown for ORP1L (Eden et al., 2016Eden E.R. Sanchez-Heras E. Tsapara A. Sobota A. Levine T.P. Futter C.E. Annexin A1 Tethers Membrane Contact Sites that Mediate ER to Endosome Cholesterol Transport.Dev. Cell. 2016; 37: 473-483Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar) to modulate the sterol content of late endosomal internal membranes, as proposed for StARD3 (Wilhelm et al., 2017Wilhelm L.P. Wendling C. Védie B. Kobayashi T. Chenard M.P. Tomasetto C. Drin G. Alpy F. STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites.EMBO J. 2017; 36: 1412-1433Crossref PubMed Scopus (118) Google Scholar), or to orchestrate nutrient signaling by delivering cholesterol to the limiting membrane to activate mTORC1 kinase, as is the case for OSBP (Lim et al., 2019Lim C.Y. Davis O.B. Shin H.R. Zhang J. Berdan C.A. Jiang X. Counihan J.L. Ory D.S. Nomura D.K. Zoncu R. ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C.Nat. Cell Biol. 2019; 21: 1206-1218Crossref PubMed Scopus (87) Google Scholar). The distribution and behavior of cholesterol in membranes depends heavily on other lipids, both in their compositions and in their dynamic arrangements between membrane leaflets and in the lateral plane of the membrane. The majority of studies on membrane lipid compositions have focused on the PM, dictated in part by convenience, i.e., its accessibility and relatively planar structure. Moreover, it is also the membrane where cholesterol not only has the highest concentration but also has important functional roles. In the PM, cholesterol partitions with sphingolipids and other saturated lipids into transient, ordered nanodomains (termed “rafts”) that affect the sorting and interactions of membrane proteins (Goñi, 2019Goñi F.M. “Rafts”: A nickname for putative transient nanodomains.Chem. Phys. Lipids. 2019; 218: 34-39Crossref PubMed Scopus (43) Google Scholar; Kusumi et al., 2020Kusumi A. Fujiwara T.K. Tsunoyama T.A. Kasai R.S. Liu A.A. Hirosawa K.M. Kinoshita M. Matsumori N. Komura N. Ando H. Suzuki K.G.N. Defining raft domains in the plasma membrane.Traffic. 2020; 21: 106-137Crossref PubMed Scopus (35) Google Scholar; Simons and Ikonen, 1997Simons K. Ikonen E. Functional rafts in cell membranes.Nature. 1997; 387: 569-572Crossref PubMed Scopus (7948) Google Scholar). Sphingolipids, with SM as the dominant species, constitute 10%–15% of PM lipids (Figure 1), and they are mostly saturated thanks to the ceramide backbone and are enriched in the exoplasmic leaflet (Figure 3). The cytoplasmic PM leaflet is approximately twofold more unsaturated than the exoplasmic one, with PS representing a dominant, highly unsaturated phospholipid class (Lorent et al., 2020Lorent J.H. Levental K.R. Ganesan L. Rivera-Longsworth G. Sezgin E. Doktorova M. Lyman E. Levental I. Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape.Nat. Chem. Biol. 2020; 16: 644-652Crossref PubMed Scopus (153) Google Scholar) (Figure 3). Phosphatidylethanolamine (PE) is also almost exclusively confined to the inner leaflet and typically polyunsaturated (Figure 3). Overall, because of these marked asymmetries, the outer PM leaflet is likely to be more packed and less diffusive than the inner leaflet (Lorent et al., 2020Lorent J.H. Levental K.R. Ganesan L. Rivera-Longsworth G. Sezgin E. Doktorova M. Lyman E. Levental I. Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape.Nat. Chem. Biol. 2020; 16: 644-652Crossref PubMed Scopus (153) Google Scholar). Despite the seminal role of cholesterol, its transbilayer distribution is not firmly established, and considering the facile flip-flop, might not be fixed (Steck and Lange, 2018Steck T.L. Lange Y. Transverse distribution of plasma membrane bilayer cholesterol: Picking sides.Traffic. 2018; 19: 750-760Crossref PubMed Scopus (63) Google Scholar). Nevertheless, significant progress in understanding cholesterol PM partitioning has been made by using protein domains from cholesterol-binding bacterial and fungal proteins as tools. This has enabled the classification of PM cholesterol into three operational pools (Figure 4). A cholesterol pool recognized by the D4 domain of perfringolysin O (PFO) and anthrolysin O (ALOD4) represents roughly 10 mol% of PM lipids (this pool becomes inaccessible when PM cholesterol falls below 30 mol%) and is highly mobile, moving rapidly to the ER to signal cholesterol surplus to the sterol-regulatory element binding protein 2 (SREBP2) machinery (Das et al., 2014Das A. Brown M.S. Anderson D.D. Goldstein J.L. Radhakrishnan A. Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis.eLife. 2014; 3Crossref PubMed Scopus (192) Google Scholar; Infante and Radhakrishnan, 2017Infante R.E. Radhakrishnan A. Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol.eLife. 2017; 6: e25466Crossref PubMed Scopus (86) Google Scholar). Ostreolysin A (OlyA) (Endapally et al., 2019Endapally S. Frias D. Grzemska M. Gay A. Tomchick D.R. Radhakrishnan A. Molecular Discrimination between Two Conformations of Sphingomyelin in Plasma Membranes.Cell. 2019; 176: 1040-1053.e17Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) and Nakanori (Makino et al., 2017Makino A. Abe M. Ishitsuka R. Murate M. Kishimoto T. Sakai S. Hullin-Matsuda F. Shimada Y. Inaba T. Miyatake H. et al.A novel sphingomyelin/cholesterol domain-specific probe reveals the dynamics of the membrane domains during virus release and in Niemann-Pick type C.FASEB J. 2017; 31: 1301-1322Crossref PubMed Scopus (22) Google Scholar) in turn recognize SM/cholesterol complexes. This pool represents about 15 mol% of PM lipids and forms the basis of the SM-sequestered pool of cholesterol (ordered nanodomain, or raft cholesterol, if you will). The remainder of PM cholesterol (about 15 mol% of PM lipids) is sequestered by other membrane factors, is critical for cell viability, and currently lacks probes. It is important to note that the cholesterol-binding protein domains are not just passive reporters of cholesterol. Rather, their binding to live cells actively configures PM cholesterol distribution: for instance, binding of OlyA to the PM outer leaflet depletes the mobile, ALOD4-accessible pool, possibly by stabilizing SM/cholesterol complexes, increasing their equilibrium distribution, and thereby depleting the uncomplexed cholesterol (Johnson et al., 2019Johnson K.A. Endapally S. Vazquez D.C. Infante R.E. Radhakrishnan A. Ostreolysin A and anthrolysin O use different mechanisms to control movement of cholesterol from the plasma membrane to the endoplasmic reticulum.J. Biol. Chem. 2019; 294: 17289-17300Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). LDL-cholesterol enters cells by receptor-mediated endocytosis of LDL, and free cholesterol released from the particles upon acid hydrolysis along the endocytic pathway accumulates in late endosomal compartments (Figure 5). The NPC1 protein in the limiting membrane of these organelles is a key gatekeeper for the release of cholesterol from lysosomes (Ikonen, 2018Ikonen E. Mechanisms of cellular cholesterol compartmentalization: recent insights.Curr. Opin. Cell Biol. 2018; 53: 77-83Crossref PubMed Scopus (34) Google Scholar). Rab GTPases and PIPs represent key players in determining endosome identities and coordinating endo-lysosomal functions (Jean and Kiger, 2012Jean S. Kiger A.A. Coordination between RAB GTPase and phosphoinositide regulation and functions.Nat. Rev. Mol. Cell Biol. 2012; 13: 463-470Crossref PubMed Scopus (127) Google Scholar). It is therefore not surprising that they also affect cholesterol delivery. Early work showed that lysosomal cholesterol export depends on the Rab GDP/GTP cycle (Hölttä-Vuori et al., 2000Hölttä-Vuori M. Määttä J. Ullrich O. Kuismanen E. Ikonen E. Mobilization of late-endosomal cholesterol is inhibited by Rab guanine nucleotide dissociation inhibitor.Curr. Biol. 2000; 10: 95-98Abstract Full Text PDF PubMed Scopus (56) Google Scholar), and overexpression of Rab proteins alleviated cholesterol accumulation in NPC1-deficient lysosomes (Choudhury et al., 2002Choudhury A. Dominguez M. Puri V. Sharma D.K. Narita K. Wheatley C.L. Marks D.L. Pagano R.E. Rab proteins mediate Golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann-Pick C cells.J. Clin. Invest. 2002; 109: 1541-1550Crossref PubMed Scopus (363) Google Scholar; Linder et al., 2007Linder M.D. Uronen R.L. Hölttä-Vuori M. van der Sluijs P. Peränen J. Ikonen E. Rab8-dependent recycling promotes endosomal cholesterol removal in normal and sphingolipidosis cells.Mol. Biol. Cell. 2007; 18: 47-56Crossref PubMed Scopus (80) Google Scholar). Recently, an activator (guanidine exchange factor complex) of Rab7 was shown to control NPC1-dependent lysosomal cholesterol export (van den Boomen et al., 2020van den Boomen D.J.H. Sienkiewicz A. Berlin I. Jongsma M.L.M. van Elsland D.M. Luzio J.P. Neefjes J.J.C. Lehner P.J. A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export.Nat. Commun. 2020; 11: 5559Crossref PubMed Scopus (19) Google Scholar). The trafficking of NPC1 organelles and at least part of LDL-cholesterol recycling toward the PM is controlled by a Rab8a-myosin Vb-actin-dependent membrane trafficking route (Kanerva et al., 2013Kanerva K. Uronen R.-L. Blom T. Li S. Bittman R. Lappalainen P. Peränen J. Raposo G. Ikonen E. LDL cholesterol recycles to the plasma membrane via a Rab8a-Myosin5b-actin-dependent membrane transport route.Dev. Cell. 2013; 27: 249-262Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). This route bears intriguing similarities to the transport of a related cholesterol transporter, NPC1L1, that is critical for cholesterol absorption in enterocytes: the recycling of NPC1L1 also requires actin and myosin Vb via the actin-binding protein LIMA (Chu et al., 2009Chu B.B. Ge L. Xie C. Zhao Y. Miao H.H. Wang J. Li B.L. Song B.L. Requirement of myosin Vb.Rab11a.Rab11-FIP2 complex in cholesterol-regulated translocation of NPC1L1 to the cell surface.J. Biol. Chem. 2009; 284: 22481-22490Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar; Zhang et al., 2018Zhang Y.Y. Fu Z.Y. Wei J. Qi W. Baituola G. Luo J. Meng Y.J. Guo S.Y. Yin H. Jiang S.Y. et al.A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption.Science. 2018; 360: 1087-1092Crossref PubMed Scopus (43) Google Scholar). The pathways that transport cholesterol downstream of NPC1 are not fully characterized. For instance, the question remained open as to which cholesterol transporters contribute to post-NPC1 cholesterol delivery to the PM. ORP2 was shown to exchange cholesterol for PI(4,5)P2 and regulate PM cholesterol levels (Wang et al., 2019Wang H. Ma Q. Qi Y. Dong J. Du X. Rae J. Wang J. Wu W.F. Brown A.J. Parton R.G. et al.ORP2 Delivers Cholesterol to the Plasma Membrane in Exchange for Phosphatidylinositol 4, 5-Bisphosphate (PI(4,5)P2).Mol. Cell. 2019; 73: 458-473.e7Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Our recent data provide evidence that ORP2-dependent cholesterol/PI(4,5)P2 exchange takes place between late and recycling endosomes, spreading LDL-derived cholesterol to recycling circuits on its way to the PM (E.I. and K. Takahashi, unpublished data). Indeed, recycling endosomes are sterol enriched (Hao et al., 2002Hao M. Lin S.X. Karylowski O.J. Wüstner D. McGraw T.E. Maxfield F.R. Vesicular and non-vesicular sterol transport in living cells. The endocytic recycling compartment is a major sterol storage organelle.J. Biol. Chem. 2002; 277: 609-617Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar) and have been implicated in cholesterol delivery. Rab11 controls cholesterol recycling (Hölttä-Vuori et al., 2002Hölttä-Vuori M. Tanhuanpää K. Möbius W. Somerharju P. Ikonen E. Modulation of cellular cholesterol transport and homeostasis by Rab11.Mol. Biol. Cell. 2002; 13: 3107-3122Crossref PubMed Scopus (108) Google Scholar), and the Rab11 and OSBP-binding protein RELCH can tether recycling endosomes and TGN to each other and facilitate OSBP-dependent cholesterol transfer to TGN (Sobajima et al., 2018Sobajima T. Yoshimura S.I. Maeda T. Miyata H. Miyoshi E. Harada A. The Rab11-binding protein RELCH/KIAA1468 controls intracellular cholesterol distribution.J. Cell Biol. 2018; 217: 1777-1796Crossref PubMed Scopus (22) Google Scholar). Upon reaching the PM, LDL-derived cholesterol is likely rapidly incorporated into cholesterol/SM complexes (Johnson et al., 2019Johnson K.A. Endapally S. Vazquez D.C. Infante R.E. Radhakrishnan A. Ostreolysin A and anthrolysin O use different mechanisms to control movement of cholesterol from the plasma membrane to the endoplasmic reticulum.J. Biol. Chem. 2019; 294: 17289-17300Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar) and replenishes the accessible pool of cholesterol that has become depleted in lipoprotein-deficient conditions (E.I. and K. Takahashi, unpublished data). Importantly, if PM PS levels are low, LDL-cholesterol accumulates in the PM and fails to reach the ER; this provides an argument that cholesterol delivery from the PM to the ER requires PS (Trinh et al., 2020Trinh M.N. Brown M.S. Goldstein J.L. Han J. Vale G. McDonald J.G. Seemann J. Mendell J.T. Lu F. Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.Proc. Natl. Acad. Sci. USA. 2020; 117: 18521-18529Crossref PubMed Scopus (33) Google Scholar). This most likely reflects the requirement of Aster/GramD proteins for PS (see below). The Aster/GramD proteins (encoded by GramD1a, b and c genes) facilitate PM-to-ER sterol trafficking (Sandhu et al., 2018Sandhu J. Li S. Fairall L. Pfisterer S.G. Gurnett J.E. Xiao X. Weston T.A. Vashi D. Ferrari A. Orozco J.L. et al.Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells.Cell. 2018; 175: 514-529.e20Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). These proteins are anchored to the ER by a transmembrane domain and contain a central cholesterol-binding StART-like/Aster domain and an N-terminal GRAM domain that binds PS and mediates Aster recruitment to PM-ER contact sites upon PM cholesterol accumulation (Figure 2B, Panel 3). Indeed, Aster proteins were shown to regulate the movement of the PM-accessible cholesterol pool to the ER (Ferrari et al., 2020Ferrari A. He C. Kennelly J.P. Sandhu J. Xiao X. Chi X. Jiang H. Young S.G. Tontonoz P. Aster Proteins Regulate the Accessible Cholesterol Pool in the Plasma Membrane.Mol. Cell. Biol. 2020; 40: e00255-20Crossref PubMed Scopus (14) Google Scholar; Naito et al., 2019Naito T. Ercan B. Krshnan L. Triebl A. Koh D.H.Z. Wei F.Y. Tomizawa K. Torta F.T. Wenk M.R. Saheki Y. Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex.eLife. 2019; 8: e51401Crossref PubMed Scopus (49) Google Scholar). Aster-dependent PM-to-ER cholesterol transfer is relevant both for the transport of HDL-derived cholesterol that is captured by SR-B1 receptors at the PM (Ikonen and Kanerva, 2019Ikonen E. Kanerva K. Shuttling HDL Cholesterol to the Membrane via Metastable Receptor Multimers.Dev. Cell. 2019; 50: 257-258Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar; Sandhu et al., 2018Sandhu J. Li S. Fairall L. Pfisterer S.G. Gurnett J.E. Xiao X. Weston T.A. Vashi D. Ferrari A. Orozco J.L. et al.Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells.Cell. 2018; 175: 514-529.e20Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar) and for the transport of LDL-derived cholesterol downstream of NPC1 after it has reached the PM (Xiao et al., 2021Xiao X. Kim Y. Romartinez-Alonso B. Sirvydis K. Ory D.S. Schwabe J.W.R. Jung M.E. Tontonoz P. Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms.Proc. Natl. Acad. Sci. USA. 2021; 118 (e2024149118)Crossref Scopus (5) Google Scholar). Recent results suggest that the GRAM domain is a co-incidence detector for cholesterol and anionic lipids, with distinct binding sites for both (Ercan et al., 2021Ercan B. Naito T. Koh D.H.Z. Dharmawan D. Saheki Y. Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b.EMBO J. 2021; 40: e106524Crossref PubMed Scopus (13) Google Scholar) (Figure 2B, Panel 3). A fraction of cholesterol is closely associated with PS (and possibly other anionic lipids, such as PIPs) without being sequestered by them, and SM can lower this codistribution due to its cholesterol sequestering potential. Vice versa, SM hydrolysis liberates cholesterol for detection by the GRAM domain (Naito et al., 2019Naito T. Ercan B. Krshnan L. Triebl A. Koh D.H.Z. Wei F.Y. Tomizawa K. Torta F.T. Wenk M.R. Saheki Y. Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex.eLife. 2019; 8: e51401Crossref PubMed Scopus (49) Google Scholar). Together, these findings support the idea that unsequestered cholesterol can rapidly exchange between the outer and inner PM leaflet. Increasing structural information on cholesterol-binding pockets of proteins will enable comparisons of cholesterol binding and release mechanisms between LTPs, such as ORD domains of ORP family, START domains of StAR family, and StART-like/Starkin/Aster domains of Aster/GramD proteins. Of note, for the newcomer, StARkin domain, an unexpected water-controlled mechanism for sterol acquisition/discharge, was recently proposed (Khelashvili et al., 2019Khelashvili G. Chauhan N. Pandey K. Eliezer D. Menon A.K. Exchange of water for sterol underlies sterol egress from a StARkin domain.eLife. 2019; 8: e53444Crossref PubMed Scopus (8) Google Scholar). Despite structural similarities between ligand binding domains, some inhibitors show selectivity among Aster/GramD proteins (Laraia et al., 2019Laraia L. Friese A. Corkery D.P. Konstantinidis G. Erwin N. Hofer W. Karatas H. Klewer L. Brockmeyer A. Metz M. et al.The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis.Nat. Chem. Biol. 2019; 15: 710-720Crossref PubMed Scopus (37) Google Scholar). In this context, it is also worthwhile to note that the compound U18666A that inhibits NPC1 (as well as select sterol biosynthesis enzymes) also inhibits Asters (Xiao et al., 2021Xiao X. Kim Y. Romartinez-Alonso B. Sirvydis K. Ory D.S. Schwabe J.W.R. Jung M.E. Tontonoz P. Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms.Proc. Natl. Acad. Sci. USA. 2021; 118 (e2024149118)Crossref Scopus (5) Google Scholar). The accessible pool of cholesterol is chemically more active than the sphingolipid-sequestered pool, and it is thus more avidly available for cytoplasmic acceptors, such as LTPs. It may also be more accessible for release out of cells, perhaps to dispose of surplus cholesterol under lipid-laden conditions (He et al., 2018He C. Hu X. Weston T.A. Jung R.S. Sandhu J. Huang S. Heizer P. Kim J. Ellison R. Xu J. et al.Macrophages release plasma membrane-derived particles rich in accessible cholesterol.Proc. Natl. Acad. Sci. USA. 2018; 115: E8499-E8508Crossref PubMed Scopus (26) Google Scholar). Interestingly, oxysterols are potent modulators of cholesterol accessibility. As little as 1% of 25-hydroxycholesterol (25-HC) can produce a detectable increase in cholesterol accessibility, probably in part through the membrane disordering effects of 25-HC (Bielska et al., 2014Bielska A.A. Olsen B.N. Gale S.E. Mydock-McGrane L. Krishnan K. Baker N.A. Schlesinger P.H. Covey D.F. Ory D.S. Side-chain oxysterols modulate cholesterol accessibility through membrane remodeling.Biochemistry. 2014; 53: 3042-3051Crossref PubMed Scopus (27) Google Scholar). Recent observations highlight how pathogens, both bacteria and viruses, including coronaviruses, rely on accessible cholesterol for cell entry (Abrams et al., 2020Abrams M.E. Johnson K.A. Perelman S.S. Zhang L.S. Endapally S. Mar K.B. Thompson B.M. McDonald J.G. Schoggins J.W. Radhakrishnan A. Alto N.M. Oxysterols provide innate immunity to bacterial infection by mobilizing cell surface accessible cholesterol.Nat. Microbiol. 2020; 5: 929-942Crossref PubMed Scopus (52) Google Scholar; Wang et al., 2020Wang S. Li W. Hui H. Tiwari S.K. Zhang Q. Croker B.A. Rawlings S. Smith D. Carlin A.F. Rana T.M. Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and other coronaviruses by depleting membrane cholesterol.EMBO J. 2020; 39: e106057Crossref PubMed Scopus (92) Google Scholar). In defense, the immune system props up the enzyme cholesterol 25-hydroxylase as one of the interferon-stimulated genes, and the produced 25-HC allosterically activates the cholesterol esterifying enzyme ACAT/SOAT (Cheng et al., 1995Cheng D. Chang C.C.Y. Qu X. Chang T.Y. Activation of acyl-coenzyme A:cholesterol acyltransferase by cholesterol or by oxysterol in a cell-free system.J. Biol. Chem. 1995; 270: 685-695Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar) and triggers rapid internalization of PM-accessible cholesterol, thus conferring resistance to pathogen entry. The ER membrane resident SOAT1/ACAT1 enzyme catalyzes the esterification of cholesterol in the ER membrane and provides an important safety valve to prevent ER cholesterol levels from rising. The generated cholesteryl esters are diffusible in the ER membrane but, via so far incompletely understood mechanisms, become packaged into LDs deriving from the ER (Thiam and Ikonen, 2021Thiam A.R. Ikonen E. Lipid Droplet Nucleation.Trends Cell Biol. 2021; 31: 108-118Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar) (Figure 2B, Panel 4). This perspective provides a brief overview of major cellular cholesterol trafficking routes, highlighting the role of the OSBP in ER cholesterol export toward the PM and Asters/GramDs in PM cholesterol import to the ER and storage of surplus cholesterol in LDs. LDL-cholesterol routing intersects with the latter circuit through the bulk of LDL-cholesterol initially directed to the PM. This safeguards PM cholesterol as a barrier and organizer of ordered domains, while the remaining, chemically active cholesterol is readily mobilized to the ER." @default.
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• W3163858333 title "Cholesterol transport between cellular membranes: A balancing act between interconnected lipid fluxes" @default.
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• W3163858333 doi "https://doi.org/10.1016/j.devcel.2021.04.025" @default.
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