Vesicular and non-vesicular lipid export from the ER to the secretory pathway

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Vesicular and non-vesicular lipid export from the ER to the secretory pathway☆ ⁎

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Kouichi Funatoa, , Howard Riezmanb, , Manuel Muñizc,d,

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a

Department of Bioresource Science and Technology, Hiroshima University, Japan NCCR Chemical Biology and Department of Biochemistry, Sciences II, University of Geneva, Switzerland c Department of Cell Biology, University of Seville, 41012 Seville, Spain d Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain b

A B S T R A C T

The endoplasmic reticulum is the site of synthesis of most glycerophospholipids, neutral lipids and the initial steps of sphingolipid biosynthesis of the secretory pathway. After synthesis, these lipids are distributed within the cells to create and maintain the specific compositions of the other secretory organelles. This represents a formidable challenge, particularly while there is a simultaneous and quantitatively important flux of membrane components stemming from the vesicular traffic of proteins through the pathway, which can also vary depending on the cell type and status. To meet this challenge cells have developed an intricate system of interorganellar contacts and lipid transport proteins, functioning in non-vesicular lipid transport, which are able to ensure membrane lipid homeostasis even in the absence of membrane trafficking. Nevertheless, under normal conditions, lipids are transported in cells by both vesicular and non-vesicular mechanisms. In this review we will discuss the mechanism and roles of vesicular and non-vesicular transport of lipids from the ER to other organelles of the secretory pathway.

1. Introduction Eukaryotic cells have an elaborate endomembrane system that makes up the secretory and endocytic pathways which is essential for cellular physiology. The secretory pathway is responsible for the biosynthesis and delivery of a third of all eukaryotic proteins from the endoplasmic reticulum (ER) to their final functional destination, either outside of the cell or in different organelles of the secretory/endocytic membrane system, including plasma membrane (PM), Golgi apparatus, endosomes and lysosome/vacuole. Newly ER-synthesized proteins are selectively transported along the secretory pathway by a series of specific vesicular trafficking events, in which lipid transport vesicles transfer them from one membrane-bound compartment to another [1]. The function of each secretory and endocytic organelle is not only defined by a specific set of proteins but also by the characteristic lipid composition and organization of their membranes. Indeed, a specific lipid composition can determine, in addition to the membrane curvature and fluidity of the organelle, the types of transmembrane proteins that will insert into the membrane and the kinds of peripherally associated proteins recruited to the cytoplasmic side. Thus, lipid composition has a crucial function in establishing membranous organelle identity and lipid diversity evolutionally conserved among eukaryotic

cells [2–5]. Lipid composition of organelles along the secretory and endocytic pathways is given by different ratios of the three major classes of eukaryote membrane lipids, glycerophospholipids, sphingolipids, and sterols. The membranes of the early secretory compartments, the ER and cis-Golgi, contain high levels of charge-paired phospholipids, such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE) (having overall neutral charge) and one anionic phospholipid, phosphatidylinositol (PI), but low levels of the other negatively charged phospholipids, phosphatidylserine (PS) and phosphatidic acid (PA). Sphingolipid and sterol levels in the ER are also low, therefore conferring relatively thin and loosely packed membranes [6]. In contrast, the PM, which is enriched in sphingolipids and sterols is much thicker and more tightly packed than the ER membranes. High levels of PS are also found in the cytosolic leaflet of the PM [2,5]. The ER is the major site of lipid synthesis and the supplier of membrane lipids to the secretory and endocytic organelles [2,5]. As such, selective and regulated lipid transport from the ER is crucial to maintain the distinct organelle compositions and identities. Once membrane lipids have been synthesized de novo in the ER by multiple biosynthetic enzymes, they are exported toward the endomembrane system via both vesicular and non-vesicular trafficking pathways

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This article is part of a Special Issue entitled Endoplasmic reticulum platforms for lipid dynamics edited by Shamshad Cockcroft and Christopher Stefan. Correspondence to: K. Funato, Department of Bioresource Science and Technology, Hiroshima University, Hiroshima 739-8528, Japan. ⁎⁎ Correspondence to: H. Riezman, NCCR Chemical Biology and Department of Biochemistry, Sciences II, University of Geneva, 1211 Geneva 4, Switzerland. ⁎⁎⁎ Corresponding author at: Department of Cell Biology, University of Seville, 41012 Seville, Spain. E-mail addresses: [email protected] (K. Funato), [email protected] (H. Riezman), [email protected] (M. Muñiz). ⁎

https://doi.org/10.1016/j.bbalip.2019.04.013 Received 23 February 2018; Received in revised form 20 December 2018; Accepted 6 January 2019 1388-1981/ © 2019 Published by Elsevier B.V.

Please cite this article as: Kouichi Funato, Howard Riezman and Manuel Muñiz, BBA - Molecular and Cell Biology of Lipids, https://doi.org/10.1016/j.bbalip.2019.04.013

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Fig. 1. Overview of lipid trafficking between the endoplasmic reticulum (ER) and secretory/endocytic organelles in eukaryotic cells. The ER is the major site of lipid synthesis. Lipids synthesized in the ER are transported to the secretory and endocytic organelles by either vesicular or non-vesicular mechanisms. Non-vesicular lipid transport between organelles is facilitated by lipid transfer proteins and/or closely apposed membrane domains known as membrane contact sites. Vesicular transport from the ER is initiated by budding of COPII-coated vesicles. Lysophospholipids appear to play a role in COPII vesicle formation. GPI-APs are segregated from transmembrane secretory proteins in the ER, and GPI-APs and very long acyl chain ceramides might be co-transported to the cis-Golgi by specialized COPII vesicles. Arrows indicate the direction of transport. Cer, ceramide; VLCer, very long acyl chain ceramide; GlcCer, glucosylceramide; GPI-APs, glycosylphosphatidylinositol-anchored proteins; GPs, glycerophospholipids; Lyso-PLs, lysophospholipids; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PI-4P, phosphatidylinositol 4-phosphate; PS, phosphatidylserine; SLs, sphingolipids.

instance for transport of sterols (cholesterol in mammalian and ergosterol in yeast cells) to the trans-Golgi network (TGN) or the PM, an import of energy is required. Different hypotheses have been put forward. In the case of transport of sterol to the PM it has been postulated that the sterol complexes with sphingolipids with saturated chains in the PM lowering the effective concentration of sterol in the compartment. The energy for transport would come from the formation of sterol-sphingolipid complexes. For sterol transport to the TGN it has been postulated that the lipid transport protein, of the oxysterol binding protein (OSBP) family, deposits sterol in the TGN where it picks up phosphatidylinositol 4-monophosphate (PI4P) and brings it back to the ER [10–12]. The PI-4P is hydrolysed to PI and phosphate. In this case the energy for transport would come indirectly from the hydrolysis of PI4P, ensuring a downhill gradient for the coupled PI-4P transport.

(Fig. 1) [7,8]. As integral constituents of the vesicle membranes, lipids can exit the ER together with the ER-synthesized proteins in transport vesicles that transfer them to the Golgi, from where they can also continue traveling along the secretory pathway by other events of vesicular trafficking or organelle maturation. However, by contrast to proteins, membrane lipids can be also directly transferred to the Golgi, PM and endosome/lysosome/vacuole by non-vesicular mechanisms that involve lipid transfer proteins and membrane contact sites between the ER and the acceptor organelles (Fig. 1 and Table 1) [9]. In this review, we will examine how membrane lipids destined to the secretory and endocytic organelles exit the ER via both non-vesicular and vesicular pathways, and how these two different export mechanisms can be coordinated to maintain organelle lipid homeostasis. 2. Non-vesicular traffic of secretory pathway lipids from the ER

2.1. Non-vesicular lipid traffic from the ER to the Golgi Most non-vesicular traffic of lipid from the ER to other cellular compartments has been proposed to occur at membrane contact sites. In principle, this process can be divided into two different mechanisms, transport with or against a concentration gradient. For the former a simple lipid transfer mechanism tending toward equilibrium could work. An example for this type of transfer could be ceramide from ER to the Golgi, because once it arrives in the Golgi it is rapidly converted to sphingomyelin or glucosylceramide in mammalian cells and inositolphosphorylceramide (IPC) in yeast cells. For the latter, for

2.1.1. Non-vesicular transport of glycerophospholipids and sterols at the ER/Golgi interface The Golgi apparatus (or Golgi complex) is an organelle that receives newly synthesized lipids and proteins from the ER, modifies them, and then distributes them to their final destinations. As genetic or pharmacologic inhibition of vesicular trafficking has no effect on transport of glycerophospholipids and sterols to the PM or only results in partial inhibition of transport [13–19], non-vesicular mechanisms, must play 2

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proteins [22]. Through these interactions on both ends of the protein, OSBP bridges the membranes between ER and trans-Golgi. Beside its ability to transfer PI4P, OSBP can also bind and transfer sterols, which led to a counterexchange model in which OSBP transfers sterol from the ER to the trans-Golgi at ER-trans-Golgi contact sites, and in turn, transfers PI-4P from the trans-Golgi to the ER [10,11]. Hydrolysis of PI4P by a PI4P-phosphatase Sac1 at the ER [23] and subsequent transfer of PI by Nir2 to the trans-Golgi enables the next round of sterol transfer by OSBP. This cycle could create the sterol gradients between the ER and the trans-Golgi [12]. This mechanism appears to be evolutionarily conserved from yeast to mammals, since Osh4, an OSBP homolog in yeast acts as a sterol/PI-4P exchanger, supplies the Golgi with sterol and functions to create a sterol gradient [24].

Table 1 Summary of discussed proteins involved in lipid transport and membrane contact site formation in mammals and yeast. Protein

Lipid transported

Membrane contact sites

ER-Golgi ER-Golgi Golgi-TGN ER-Golgi, ER-PM ER-PM ER-PM ER-PM ER-PM ER-PM ER-PM, ER-LE

ORP8 ORP2 GRAMD1a GRAMD1b GRAMD1c GRAMD2a ABCA2 ABCA3 ABCA12 ABCB1 ABCG1 Protrudin Rab7 Annexin A1 S100A11 ORP1L ORP6 STARD3 VPS13A VPS13C

PI4P, sterol Cer GlcCer PI, PA PI, PA PE, PC, PS, DAG ? ? PI PS, PI4P, PI(4,5)P2, Sterol PS, PI4P, PI(4,5)P2 Sterol Sterol Sterol Sterol ? SM SM Cer SM, GSL SM – – – – Sterol (?) Sterol Sterol PC, PE, PS, PA ?

Yeast Osh4 (OSBP homolog) Nvj2

PI4P, Sterol Cer Cer (?)

ER-Golgi ER-Golgi, perinuclear ERvacuole ER-Golgi

PS, PI4P PS, PI4P Sterol PI4P (?), sterol Sterol

ER-PM ER-PM ER-PM ER-PM ER-PM

Sphigoid bases – – Cer (?) – – – Sterol ? – Sterol

ER-PM ER-PM ER-PM ER-PM Perinuclear Perinuclear Perinuclear Perinuclear Perinuclear Perinuclear Perinuclear

– –

Perinuclear ER-vacuole Perinuclear ER-vacuole

Mammalian OSBP CERT FAPP2 Nir2 Nir3 E-Syt1 E-Syt2 E-Syt3 TMEM24 ORP5

Ltc2/Lam5 (GRAMD protein homolog) Osh6 (OSBP homolog) Osh7 (OSBP homolog) Osh2 (OSBP homolog) Osh3 (OSBP homolog) Ltc4/Lam2 (GRAMD protein homolog) Rsb1 Tcb1 (E-Syt homolog) Tcb2 (E-Syt homolog) Tcb3 (E-Syt homolog) Nvj1 Vac8 Tsc13 Osh1 (OSBP homolog) Vps13 (VPS13 homolog) Ypt35 Ltc1/Lam6 (GRAMD protein homolog) Mdm1 Nvj3

ER-PM ER-PM ER-PM ER-PM ER-PM ER-PM – – – – – ER-LE ER-LE ER-LE ER-LE ER-LE ER-EE ER-E ER-E ER-E

2.1.2. Non-vesicular transport of ceramide in mammalian cells Ceramide synthesized in the ER is transported to the Golgi via either vesicular or non-vesicular routes (Fig. 2) [8,25–28]. In mammals, since glucosylceramide and sphingomyelin are synthesized on the Golgi apparatus, ceramides used for their synthesis must be delivered to the Golgi compartments. Conversion of ceramide to glucosylceramide appears to be ATP-independent [29], which may suggest that ceramide used for glucosylceramide synthesis is transported to the Golgi by a non-vesicular mechanism. Ceramides are also delivered to the site of sphingomyelin synthesis by a non-vesicular pathway [26–28,30]. The delivery of ceramides for sphingomyelin synthesis requires the ceramide transfer protein CERT [31]. CERT, like OSBP, contains a PH domain, an FFAT domain and a START family domain that transfers ceramide. Thus, it is believed that CERT-mediated ceramide transfer occurs at ER-trans-Golgi membrane contact sites [32]. Of note, recruitment of CERT to the Golgi is stimulated via regulation of PI-4P levels by OSBP, thereby facilitating the CERT-dependent ceramide transport [8,33,34]. These findings suggest that OSBP forms a functional link between sterol and sphingolipid metabolism. Sphingolipid metabolism is also linked to glycerophospholipid metabolism, as sphingomyelin synthase produces diacylglycerol from PC [35] and sphingomyelin regulates the transbilayer movement of diacylglycerol in the plasma membrane [36].

2.1.3. Non-vesicular transport of ceramide in yeast cells The budding yeast S. cerevisiae uses both vesicular and non-vesicular pathways for conversion of phytoceramide to IPC in the Golgi (Fig. 2) [37]. IPC synthesis takes place in the lumen of the medial-Golgi [38]. In contrast to the COPII-mediated transport, non-vesicular ceramide transport occurs in an ATP-independent manner [37]. An in vitro biochemical assay, which measures in vivo the ATP-independent ceramide transport activity, revealed that non-vesicular ceramide transport requires an unidentified cytosolic protein (s) and contact sites between the ER and the Golgi. Recently, Nvj2 was identified as a tethering factor that promotes non-vesicular ceramide transport [39]. It was revealed that Nvj2 becomes enriched at ER-Golgi contacts at times of ER stress or when vesicular trafficking from the ER is compromised. Considering that Nvj2 overexpression increases contacts between the ER and the medial-Golgi where IPC synthase Aur1 is mainly localized, and that lysates from cells overexpressing Nvj2 result in an increased activity for in vitro ceramide transport, it seems that Nvj2 serves as a tether that facilitates non-vesicular ceramide transport to the Golgi, which could compensate for impaired vesicular transport. Congruent with the function of Nvj2, the authors also showed that Nvj2 plays an important role in preventing toxic accumulation of ceramide. Interestingly, in nvj1Δ cells where Nvj2 relocalizes to the ER-Golgi contact sites, Nvj2 is colocalized with Ltc2/Lam5, which is a conserved family membrane of sterol transport proteins (Ltc/Lam), suggesting that Lam5 may be involved in regulating ceramide transport at the ER-Golgi contact sites [40].

ER-vacuole ER-vacuole ER-vacuole ER-vacuole ER-vacuole ER-vacuole ER-vacuole

an important role for transport of lipids between the ER and the Golgi and be able to compensate for the loss of vesicular transport. The Golgi is also one of the main sites of PI-4P synthesis. It has been proposed that a PI-transfer protein, Nir2 delivers PI to the trans-Golgi by a non-vesicular pathway to convert it to PI-4P [20]. As Nir2 transfers PI to the Golgi for PI-4P biosynthesis, the function of Nir2 is coupled with other lipid transfer proteins such as OSBP, which contains an N-terminal pleckstrin homology (PH) domain that interacts with the Golgi PI-4P [21]. OSBP, in addition to the PH domain, contains a phenylalanine–phenylalanine-acidic-tract (FFAT) motif that interacts with the integral ER VAP (vesicle-associated membrane protein-associated protein) 3

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Fig. 2. Comparative biosynthetic pathways of sphingolipids in yeast and mammalian cells. Ceramide is synthesized de novo in the ER, from where is delivered to the Golgi to serve as the precursor of complex sphingolipids in both yeast and mammalian systems. Yeast cells produce almost exclusively very long acyl chain phytoceramide (C26) (phyCer), which is mainly transported to the cis-Golgi by COPII vesicles, then converted in the medial-Golgi to inositolphosphoceramides (IPC) by Aur1 and then mannosylated into MIPC and M(IP)2C. A smaller proportion (20–30%) of phyCer is directly delivered to the medial-Golgi via non-vesicular transport by Nvj2. Mammalian cells, unlike yeast, generate several types of ceramides (Cer) with different acyl chain lengths. Most of de novo synthesized Cer is directly transferred via non-vesicular transport to the trans-Golgi by the lipid transfer protein CERT to primarily produce sphingomyelin (SM). CERT displays a preference for Cer species with acyl chains less than C22. A smaller portion of de novo synthesized Cer is destined to the cis-Golgi for glucosylceramide (GlcCer) synthesis. Only very long acyl chain ceramide (C24) appears to be vesicularly transported to the cis-Golgi via the ER-Golgi intermediate compartment (ERGIC). Instead, the shorter ceramides are likely delivered via an unknown non-vesicular mechanism (?) to the cis-Golgi for GlcCer synthesis. These GlcCer are further glycosylated by two different glycosylation intra-Golgi pathways involving vesicular and non-vesicular FAPP2 proteindependent pathways. Through these differential processing, GlcCer are finally transformed into a series of complex (GSLs).

phosphoinositides exchangers to supply the PM with PS and the ER with PI-4P or PI(4,5)P2 [24,55,56]. The yeast OSBP homolog proteins, Osh6 and Osh7 are capable of exchanging PS and PI-4P at the ER-PM contact sites [24,57].

2.2. Non-vesicular lipid traffic from the ER to the PM 2.2.1. Non-vesicular transport of glycerophospholipids at the ER/PM interface in mammalian cells Lipids synthesized in the ER can be directly delivered to the PM by non-vesicular pathways. Non-vesicular delivery of lipids is enhanced at ER-PM contact sites formed by protein tethers [10,41–45]. The advantage of protein-mediated lipid transport at membrane contact sites has been recently proposed to be not only the speed but also the accuracy of delivery [28,46]. One class of such tethers contains a lipid transport module, called the SMP (synaptotagmin-like, mitochondrial and lipid-binding proteins) domain [41,44,47,48]. Mammalian extended-synaptotagmins (E-Syts) that have a SMP domain and multiple C2 domains are localized at contacts between the ER and the PM. As they transfer glycerophospholipids in vitro via their SMP domains, it has been proposed that E-Syts could play a role in bulk transfer of glycerophospholipids between the ER and the PM [49,50]. Another SMP domain-containing protein, TMEM24, is targeted to ER-PM contacts, and preferentially binds and transports PI [51], suggesting that it delivers newly synthesized PI from the ER to the PM. Other lipid transfer proteins, which have no SMP domain but are localized to ERPM contact sites, are Nir proteins and ORP/Osh proteins. Nir2 and Nir3 possessing PI transfer protein (PIPT) domains at their N termini play an important role in the maintenance of PI-4P and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) pools via their PI transfer function at ERPM contact sites [44,52]. Nir2 translocates from the Golgi to the PM in response to PA production [53]. Nir2 was found to deliver PA from the PM to the ER for PI synthesis [54]. It was thus proposed that Nir2 functions as a PA/PI exchanger [44]. ORP5 and ORP8 act as PS/

2.2.2. Non-vesicular transport of sterols at the ER/PM interface in yeast cells The discovery of sterol and PI-4P binding and transfer activity of Osh4 suggested that the function of yeast Osh proteins could be to exchange sterol and PI-4P between the ER and the PM [21,58,59]. However, the bidirectional movement of sterols between the ER and PM was not affected in a temperature-conditional yeast mutant lacking all functional Osh proteins [60]. Intriguingly, Osh proteins were found to regulate the organization of sterols at the PM. Sterol/PI-4P exchange mediated by Osh4 might be used to supply the post-Golgi vesicles with sterol, thereby ensuring an appropriate sterol organization of the PM [59]. Work by the group of Bankaitis indicated that Osh4 contributes to regulation of TGN/endosome-derived PI-4P/sphingolipid signaling [61]. Moreover, Stefan et al., reported that Osh2 and Osh3, which localize to the ER-PM contact sites, function as regulators of PI-4P metabolism [62]. Interestingly, these Osh proteins mediate ER contact with endocytic sites and Osh2 sterol transfer domain facilitates actin polymerization [63]. Osh3 was also shown to recruit the ER enzyme Opi3 for PC synthesis to ER-PM contact sites [64], although one cannot rule out the possibility that Osh2 and Osh3 could function as lipid transporters. A mammalian homolog of Osh proteins, ORP2 has been proposed to function as a sterol transporter between the ER and the PM [21,65,66]. Interestingly, yeast endocytic invaginations associate with the ER and that this association specifically requires the ORPs Osh2 and 4

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transport from the ER. In addition, recent studies provide evidence that Vps13 functions as a lipid transporter in the nonvesicular transport of glycerophospholipids at ER-endosome contact sites [94].

Osh3. In addition to Osh/ORP proteins, an Ltc/Lam family member, Ltc4/ Lam2/Ysp2 specifically binds sterols and localizes to ER-PM contact sites [67]. In cells that lacked yeast Ltc4 protein, the rate of esterification of exogenously supplied fluorescent sterol dehydroergosterol (DHE) was reduced, suggesting that Ltc4 may play a role in sterol transport from the PM to the ER at their contact sites [68]. A slow rate of DHE esterification is also observed in cells lacking ER-PM contact sites [69]. Similar mechanisms for sterol transport may operate in mammalian cells, because the human Ltc/Lam protein orthologs, GRAMD1a and GRAMD2a also localize to ER-PM contact sites [70], and GRAMD1a, 1b and 1c (referred to as Aster proteins, Aster-A, -B, and -C) have the capacity to mediate sterol transport between the ER and the PM [71].

2.3.2. Non-vesicular transport of sterols and sphingolipids at the ER/ vacuole interface in yeast cells In yeast, contact sites between the perinuclear ER (nuclear envelope) and the vacuole, namely the nucleus-vacuole junction (NVJ), are formed through the interaction of the ER membrane protein Nvj1 with Vac8, a palmitoylated vacuolar protein [95]. NVJ is the first reported example of ER-organelle contact site, and many other proteins localized to NVJ have been identified. They include Nvj2, Tsc13 (an enoyl reductase), Osh1, Vps13, Ypt35 (a vacuolar adaptor for Vps13) [80,81,85,96]. Murley et al. showed that an ER protein, Ltc1 localizes to both NVJs and other non-NVJ ER–vacuole contact sites and has the ability to catalyze sterol transfer between membranes in vitro [97]. The authors also found that exclusive localization of Ltc1 to ER–vacuole contacts induces sterol-enriched domain formation in the vacuolar membrane. Thus, these observations suggest that Ltc1 has a role in ERto-vacuole transport of sterols at contact sites. Like Nvj1, Ltc1 binds to Vac8 to localize to ER–vacuole contact sites. Vac8 targets to the vacuole membranes via its palmitoylation [98]. Given that palmitoylation specifically targets Vac8 to sterol and sphingolipid-enriched domains on the vacuolar membranes [99], formation of Vac8-dependent contact sites probably occurs at specific membrane domains. Furthermore, yeast Osh1, a structural homolog of ORP1L, may be involved in sterol transfer between the ER and the vacuole [21]. In addition to these NVJ-localized proteins, a conserved ER-endosomal organelle tethering protein Mdm1 and its binding partner Nvj3 were identified [41]. Mdm1 is anchored in the ER by its transmembrane region and localizes to the NVJ through binding of its Phox (PX) domain to vacuolar PI3P. Overexpression of Mdm1 hypertethers the ER and vacuole, suggesting that Mdm1 functions as a tether between these organelles. Intriguingly, loss of the PX domain that is necessary for Mdm1-mediated ER-vacuole tethering confers hypersensitivity to myriocin, suggesting that it perturbs sphingolipid metabolism. The ER-vacuole contact sites might play a role in sphingolipid transfer from the ER to the vacuole or in recycling of sphingolipid breakdown products to the ER. In connection with this, it is interesting to note that Tsc13, which is involved in the synthesis of long chain ceramides [80] and Nvj2, which is involved in ER-to Golgi non-vesicular transport of ceramide, are enriched at the NVJ [76].

2.2.3. Non-vesicular transport of sphingolipids from the ER to the PM in yeast cells Members of the ATP-binding cassette (ABC) superfamily, localized to the PM, are involved in lipid efflux across the PM [72–74]. In addition to phospholipid and sterol efflux, some ABC transporters appear to be required for the outward translocation of sphingolipids such as ceramide, sphingosine-1-phosphate, and glucosylceramide. In yeast, Rsb1 has also been shown to be involved in the export of ceramide precursors, long chain sphingoid bases (dihydrosphingosine and phytosphingosine) [75]. As long chain sphingoid bases, ceramide, and sphingosine-1-phosphate are synthesized in the ER, delivery of these sphingolipids to the PM may occur at ER-PM contact sites by a nonvesicular pathway. Loss of Osh2, Osh3 or tricalbin proteins (Tcb1, Tcb2, and Tcb3; yeast orthologs of E-Syts) leads to an altered sensitivity to inhibitors of sphingolipid synthesis enzymes (myriocin, aureobasidin A) [76,77]. Tcb3 appears to be capable of binding to ceramide [78] and cells lacking the ER-PM tether proteins including Tcb proteins display an alteration in sphingolipid metabolism [79]. These findings raise the possibility that Osh and Tcb proteins may be involved in non-vesicular transport of sphingolipids between the ER and the PM. 2.3. Non-vesicular lipid traffic from the ER to the endosome/lysosome/ vacuole 2.3.1. Non-vesicular transport of sterols at the ER/endosomal compartment interface in mammalian cells Endosomes and lysosomes (vacuoles in yeast) can establish contact sites with the ER [80–85]. Their contact sites facilitate non-vesicular sterol transport between the ER and the endocytic organelles. In mammalian cells, protrudin, an integral VAP-A binding protein that binds early an endosomal lipid, phosphatidylinositol 3-monophosphate (PI3P) and a late endosomal protein, Rab7, forms an ER-endocytic organelle contact site [86]. Annexin A1 and its calcium-dependent ligand S100A11 also function as tethers to establish contact sites between the ER and multivesicular endosomes/bodies (MVBs) [87]. Annexin A1regulated contacts are required for transfer of ER-derived sterol to MVBs and this sterol transfer depends on direct VAP-ORP1L interaction, which is formed under conditions of low endosomal sterol. ORP1L senses endosomal sterol levels and localizes to late endosome via interaction with Rab7 [88]. Although a direct role of ORP1L in sterol transfer remains to be elucidated, the formation of ER-late endosome contact sites by ORP1L and VAP is required for sterol transport from the ER to the late endosome under low sterol conditions [87]. ORP1L is also involved in retrograde sterol transport from the late endosome to the ER [89]. Other ORPs, ORP5 and ORP6 appear to be implicated in sterol transport to the ER from the late endosome and early endosome, respectively [90,91]. Like ORP1L, a START-domain protein, STARD3 functions in ER-to-endosome sterol transport across the contact sites formed by interaction with VAP [92]. Intriguingly, STARD3 and ORP1L were found to localize to different endosomal populations [93], suggesting that they may participate in parallel pathways for sterol

3. Lipids and COPII vesicle dynamics Vesicular trafficking along the secretory pathway is a major mechanism of protein and lipid delivery required for biogenesis and homeostasis maintenance of the endomembrane system [5]. Vesicles can transport bulk amounts of lipids bidirectionally from one organelle to another as they are basic constituents of the vesicle membrane. However, lipids are far from just passive passengers of transport vesicles with the simple structural role of sealing the carrier compartment [2]. Now it is increasingly clear that they can play active roles in vesicular trafficking like facilitating the recruitment of specialized cytosolic proteins of the transport machinery or increasing the membrane curvature to generate the vesicle bud. Moreover, segregation of membrane lipids into different fluid phases has been also suggested as a sorting mechanism for lipids and proteins. Lipid sorting upon vesicular transport could contribute, for example, to an enrichment of sphingolipids and sterols along the secretory pathway by their preferential incorporation into anterograde transport vesicles or by their exclusion from retrograde transport vesicles. Consistent with this, in mammalian cells retrograde transport vesicles derived from the Golgi contain, in general, a lower level of sphingolipids and cholesterol than the donor Golgi membranes [100] and, conversely, anterograde secretory vesicles in yeast have a higher level of sterol and sphingolipids than their 5

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local membrane deformation at ERES in two complementary ways. First, the activated form of the GTPase Sar1 could directly initiate membrane curvature during vesicle biogenesis by lowering the membrane bending rigidity upon membrane insertion of its N-terminal amphipathic α helix, which has been shown to deform synthetic liposomes into narrow tubules [110,111]. On the other hand, the recruitment and assembly of the rigid COPII coat formed by Sec23/24 and Sec13/31 heterocomplexes also bend the ER membrane to generate the vesicle. Sec31 is the essential structural component forming the polyhedral cage-like structure and Sec13 appears to help Sec31 to bend the membrane by rigidifying the coat [112,113]. Membrane bending upon cargo capture at ERES represents a difficult task for the COPII machinery, especially considering that cargo crowding in the vesicular lumen opposes membrane bending by coat proteins [112]. Thus, COPII machinery may require help to accomplish the mechanical deformation of the ER membrane [114]. Since membrane bending rigidity is determined by lipid composition [115], the local accumulation at the ERES of specific lipids that increase membrane flexibility could facilitate COPII-mediated membrane deformation. This potential role has been assigned to conical lipids such as the lysophospholipids [105,116], which are glycerophospholipids with only a single acyl chain linked to the glycerol backbone that can be generated by specific phospholipases [117]. The conical shape of these lipids is thought to facilitate vesicle formation by increasing curvature or membrane fluidity [105,118,119]. Early studies already linked conical lipids with COPII function. Mammalian phospholipase A1 protein p125 was identified as a binding partner of COPII subunits and localized to ERES, suggesting the specific presence of lysophospholipids at the ERES [120,121]. This key prediction has been recently confirmed by Melero et al. using the yeast system. They performed a lipidomic analysis of in vitro produced COPII vesicles from yeast ER microsomes showing specific enrichment in lysophospholipids, especially lysoPI and lysoPC [105]. These two lysophospholipids are the most conical phospholipids in the yeast cell when compared to other lysophospholipids. Furthermore, increasing the levels of lysoPI in yeast cells by overexpressing the phospholipase Plb3 or by deletions of the lipid transferases osh2, osh3, and osh4, can rescue the growth of the COPII mutant sec12-4 temperature-sensitive cells at non-permissive temperature [77,105]. Since Sec12 is the essential activator of Sar1 required for COPII assembly, this evidence suggests that lysoPI levels could facilitate budding under conditions of defective COPII coat dynamics, such as low levels of Sar1-GTP, which links lyso-PI with COPII vesicle formation. Moreover, in vitro reconstituted COPII binding onto giant liposomes with purified yeast proteins showed that lysoPI decreases membrane bending rigidity and enhances Sar1 and the COPII coat recruitment to liposomes [105], which agrees with previous studies using other types of lysophospholipids [116]. Therefore, conical lysophospholipids appear to play a role in COPII vesicle formation by increasing the elasticity of ER membrane at the ERES and facilitating the interaction of COPII proteins with the outer leaflet.

parental trans-Golgi membranes [101]. The starting point of the secretory pathway is the ER, from where newly synthesized and correctly folded proteins travel with membrane lipids in transport vesicles to the next station, the cis-Golgi compartment in yeast, or the ER-Golgi intermediate compartment (ERGIC) in mammalian cells. These vesicles are generated by polymerization of cytosolic coat protein complex COPII, which locally bends the ER membrane at specific spots called ER exit sites (ERES) [102,103]. The COPII coat is highly conserved from yeast to mammals and comprises the small GTPase Sar1 and the two protein heteromeric complexes Sec23/24 and Sec13/31. COPII coat assembly is initiated when Sar1, upon activation by its GEF the transmembrane protein Sec12, recruits first the heterodimer Sec23/24 to the ERES. Then, the subcomplex Sar1-GTP-Sec23/24 or inner COPII coat layer captures the protein cargo and acts as a platform to, in turn, recruit the heterotetramer Sec13/31 or outer COPII coat layer, which polymerizes to form a cage-like structure that eventually bends the membrane of the nascent vesicle. The COPII machinery is expected to export a large amount of lipids from the ER membrane at very high rate, as it has been estimated by measuring the bulk flow transport of a soluble protein in mammalian cells, that at least half of the lumenal volume of the ER is drained out by vesicles in about 40 min [104]. This intense anterograde lipid flow is compensated by a vesicular retrograde transport from the cis-Golgi to maintain the ER integrity. Lipids synthesized in the ER show differential requirements for COPII-dependent export [19]. Glycerophospholipids are the most abundant components of the ER membrane at steady state in both yeast and mammalian systems. In yeast, a recent lipidomic analysis of COPII vesicles, generated through in vitro budding assays using ER microsomes with purified COPII components, has shown that the levels of major glycerophospholipids PC, PE and PI did not change substantially in budded vesicles with respect to the ER microsomes except for PS, whose abundance is significantly reduced in microsomes post-budding and COPII vesicles [105]. Therefore, in yeast, non-selective bulk-flow appears to be a mechanism for incorporating most major glycerophospholipid species of the ER membrane into COPII vesicles. In contrast to major glycerophospholipids, ceramide and sterol concentrations remain low in the ER, as most of them are exported to the late secretory pathway in both yeast and mammalian systems. In yeast, whereas phytoceramides synthesized de novo in the ER are transported to the Golgi by both COPII-dependent vesicular transport and COPII-independent non-vesicular transport [25,37], de novo synthesized sterols seem to be preferentially exported from the ER by non-vesicular mechanisms [18]. In mammals, de novo synthesized ceramides and cholesterol primarily exit the ER via non-vesicular pathways [29,31], although a portion of ceramides with very long acyl chain might be exported in COPII vesicles [106]. Cholesterol synthesis and homeostasis maintenance depend on a sophisticated regulatory mechanism involving COPII dependent vesicular transport [107]. 3.1. Lysophospholipids, membrane curvature and COPII vesicle budding

3.2. COPII vesicle export of ceramides and GPI-anchored proteins Generation of COPII-coated vesicles is a biophysical process that couples mechanical deformation and bending of the ER membrane at ERES to protein cargo capture. Interestingly, although the structural organization of ERES remains elusive, in yeast, their distribution depends on de novo fatty acid synthesis [108] and they localize to highcurvature ER domains, such as ER tubules and the edges of ER sheets, where the reticulon Rtn1, a curvature-stabilizing protein, is present [109]. Even when the number of high-curvature ER domains was greatly reduced in yeast cells by the combined absence of reticulons (Rtn1 and Rtn2) and the other curvature-stabilizing protein Yop1, ERES still accumulate at the few remaining high-curvature ER domains on the edge of expanded ER sheets. This clear preference of ERES for highly curved regions of the ER membrane is thought to facilitate the vesicle budding activity of the COPII machinery, which can also contribute to

In addition to the non-vesicular pathway described above, de novo synthesized ceramide in the ER can also be delivered by COPII vesicles to the cis-Golgi to serve as the precursor of complex sphingolipids (Fig. 2). This vesicular pathway could be preferentially exploited by very long acyl chain ceramides due to their inherent difficulty to undergo non-vesicular transport. Indeed, yeast cells produce almost exclusively very long acyl chain phytoceramide (C26), which has been shown to be mainly transported from the ER to the cis-Golgi by COPII vesicles [37]. In contrast, mammalian cells generate several types of ceramides with different acyl chain lengths destined to the cis-Golgi for glucosylceramide synthesis. Whereas shorter acyl chain ceramides are most likely delivered to the cis-Golgi by a non-vesicular mechanism, very long acyl chain ceramides (C24) seem to be exported in COPII 6

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mentioned above, from the different types of ceramides produced by mammalian cells, just the synthesis of very long acyl chain glucosylceramides at the cis-Golgi depends on GPI biosynthesis, suggesting that their precursor ceramides might be co-transported with GPI-APs in the same COPII vesicles. However, this association would not be sufficient to sort mammalian GPI-APs into specific ERES and COPII vesicles like in yeast, since in mammalian cells GPI-APs have been found to be concentrated in the same ERES together with other secretory proteins [140] at least with the resolution available at the time of these experiments. Regardless of this, mammalian GPI-APs are sorted later from other secretory proteins at the level of the TGN, where they are segregated into different secretory vesicles that follow separate routes to the cell surface [142]. In most polarized epithelial cells, this sorting step delivers the GPI-APs to the apical membrane and can be specifically impaired by inhibitors of sphingolipid biosynthesis and/or removal of cholesterol [143–145]. Interestingly, this sorting step correlates with the GPI-lipid remodeling that, unlike yeast, occurs in the Golgi and consists of the acquisition of a saturated fatty acid in the sn-2 position of the GPI anchor [124]. This correlation has led to the proposal of a lipidbased mechanism for apical sorting of GPI-APs from the TGN that could be, somehow, analogous to the ER sorting mechanism proposed in yeast [130,146,147]. It is postulated that GPI-lipid remodeling in the Golgi would lead GPI-APs to cluster and associate through the two saturated fatty acids with sphingolipids and cholesterol into specialized lipidordered domains which would serve as selective platforms for vesicle budding at the TGN. However, the postulated role of GPI-lipid remodeling in apical sorting is not completely clear yet, since recent evidence suggest that lyso-GPI-APs are apically sorted, although this sorting is still sensitive to depletion of cholesterol [148]. It is possible that this mechanism normally plays and important role that is covered by additional redundant apical sorting mechanisms that drive apical sorting of GPI-Aps.

vesicles. This possibility is inferred from the observation that only the synthesis of very long acyl chain glucosylceramides at the cis-Golgi depends on the biogenesis glycosylphosphatidyl inositol (GPI) anchors used to attach a class of secretory proteins, GPI-anchored proteins (GPIAPs), to the membrane in the ER [106]. A similar requirement has also been observed in yeast for IPC formation at the cis-Golgi [122], suggesting that very long acyl chain ceramides might be co-transported with these secretory proteins in the same COPII vesicles in both yeast and mammalian systems [123]. GPI-APs are lipid-anchored cell surface proteins expressed from yeast to human that includes a wide diversity of receptors, adhesion molecules, and enzymes [123]. GPI-APs are attached to the external leaflet of the plasma membrane via a post-translational glycolipid modification, the GPI anchor. The core structure of the GPI anchor precursor is largely conserved in evolution and consists of a phospholipid moiety with a glycan backbone. Once the GPI anchor precursor has been made by a series of sequential reactions at the ER membrane, it is then attached en bloc in the ER lumen by a GPI-transamidase complex to newly synthesized proteins containing a cleavable GPI attachment signal sequence at their C terminus. Immediately after attachment to the protein, the structure of the lipid and glycan parts of the GPI anchor are modified by several remodeling enzymes [124]. Remodeled GPI-APs are recognized by the transmembrane p24 protein complex that link GPI-APs with the specific isoforms of the COPII cargo binding subunit Sec24, Lst1 in yeast or Sec24C and Sec24D in mammals, for their efficient incorporation into COPII vesicles and subsequent ER export [125–129]. 3.2.1. GPI-lipid remodeling and sorting of GPI-APs in yeast cells The presence of the GPI anchor endows GPI-APs with an exclusive mode of membrane association within the lumen of secretory organelles that leads them to be trafficked differently than transmembrane secretory proteins [130]. Indeed, in yeast GPI-APs are segregated from transmembrane secretory proteins in the ER, and subsequently incorporated into distinct COPII vesicles [131]. This sorting process upon exit from the ER could be driven by a lipid-based mechanism, which includes the structural remodeling of the lipid moiety of the GPI anchor [132]. In yeast, GPI-lipid remodeling begins immediately after the GPI anchor is attached to the nascent protein and has the final purpose of incorporating ceramide, a very long chain and saturated lipid, to the GPI anchor. The remodeling process consists of inositol deacylation by Bst1, followed by fatty acid remodeling, which involves the removal of the unsaturated fatty acid at the sn2 position by Per1 and its replacement with a very long-chain saturated fatty acid (C26) by Gup1 [133–135]. Finally, the C26 diacylglycerol formed as part of the anchor is replaced with a ceramide that also contains a very long-chain saturated fatty acid (C26), by Cwh43 [136,137]. In yeast, ER exit of GPIAPs requires ongoing synthesis of phytoceramide and IPC formation at the Golgi depends on the GPI anchor synthesis [138]. Therefore, these data indicate that ceramides and lipid-remodeled GPI-APs might cooperate to be co-sorted at specific ERES, from where they can be cotransported to the cis-Golgi by specialized COPII vesicles. The fact that both ceramides and lipid-remodeled GPI-APs contain a very long saturated fatty acid (C26) in contrast to the ER glycerolipids (C16 and C18), might favor their selective clustering by self-assembly at specific ER membrane domains [123,130]. In artificial membranes, biophysical experiments suggest that ceramides can coalesce to form platforms with specific physical properties [139].

3.3. ER sterol and COPII vesicular transport Newly synthesized sterol is thought to be mainly transported out of ER to the plasma membrane by non-vesicular transport mechanisms. In yeast there is no defect in sterol transport rate in secretory mutants such as sec18, which blocks almost all intracellular vesicular trafficking events [18]. The rapid export requires sterol transport proteins (STPs) and results in the low sterol content (5 mol% of total lipid) in ER membrane at steady state, which produces a loose lipid packaging that facilitates ER basic functions such as the insertion of nascent transmembrane proteins [27,149]. Nevertheless, the ER-localized pool of sterol can also play important roles. In mammalian cells, the ER cholesterol has been shown to be required for efficient ER-to-Golgi transport of secretory membrane proteins including GPI-APs, the vesicular stomatitis virus glycoprotein (VSVG) and the scavenger receptor A [128,149,150]. In the case of VSVG, cholesterol could regulate its incorporation into ER exit sites by favoring lateral mobility and/or by controlling membrane turnover of specific COPII subunits [149,150]. Unlike mammalian cells, the ER-to-Golgi transport of GPI-APs is unaffected in yeast sterol synthesis mutants [151]. Nevertheless, in GPI anchor synthesis mutants in yeast, sterols accumulate in the ER and in lipid particles [122]. Because in the same yeast mutants, sphingolipid biosynthesis is strongly affected, it has been proposed that non-vesicular trafficking of sterols is required to maintain an equilibrium between free sterols and sterols complexed with sphingolipids at the plasma membrane [18,152]. Another key function of the sterol present in the ER is to regulate expression of genes involved in sterol synthesis, uptake and other lipid synthesis pathways. In mammalian cells the ER level of cholesterol is maintained through a sophisticated system involving the regulated COPII vesicular export of a membrane-bound transcription factor of the sterol regulatory element-binding protein (SREBP) family [153]. Newly synthesized SREBPs constitutively bind in the ER to SCAP, which is a

3.2.2. GPI-lipid remodeling and sorting of GPI-APs in mammalian cells In mammalian cells, in contrast to yeast, the ER-to-Golgi transport of GPI-APs does not require de novo ceramide synthesis [140]. This is likely due to the fact that mammalian ceramides are mainly exported from the ER to the Golgi by non-vesicular transport mechanisms [31,141], but also because the specialized lipid structure of GPI anchors is ether-lipid based in animals rather than ceramide-based in yeast. As 7

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Foundation [to HR] and by the grant from the Spanish Ministry of Economy and Competitiveness (MINECO) BFU2017-89700-P [to MM].

polytopic protein with eight transmembrane helices containing a ‘sterol-sensing’ region. When sterol levels are high, the SCAP/SREBP complex is specifically retained in the ER by the interaction with the ER resident protein Insig through its ‘sterol-sensing’ region. However, upon ER sterol depletion, SREBP-SCAP is released from Insig, which is degraded by the ER-associated degradation (ERAD) machinery, allowing COPII subunits to bind to SCAP's MELADL cytosolic sequence which facilitates COPII vesicular delivery of SCAP/SREBP to the Golgi [107,154]. Once in the Golgi, SREBP is proteolytically processed by Site-1 and Site-2 proteases, releasing the transcription factor domain of SREBP [155]. The SREBP transcription factor is then translocated to the nucleus for transcription of the genes of cholesterol synthesis and uptake, which increases cholesterol levels to restore homeostasis [153]. It is not clear, how in the sterol depletion state, the COPII-mediated export from the ER is stimulated for the SCAP/SREBP complex but reduced for secretory membrane proteins as mentioned above.

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4. Conclusion Two different mechanisms export newly synthesized lipids from the ER toward the secretory/endocytic system. Extensive efforts have recently revealed that sterols, ceramides and glycerophospholipids can be directly and rapidly exchanged by specific lipid transfer proteins at membrane contact sites between the ER and the other organelles of the pathway. While the basic principle of lipid transport proteins acting at membrane contact sites seems to be established, we do not know the quantitative and qualitative contribution of the pathways in cells because methods to measure lipid transport between organelles in vivo are lacking. Recent use of organelle targeted, caged, photoactivatable isotope-labeled lipids should help to solve this problem [156,157]. While this area is exciting and important, these lipids can also be exported by COPII-coated vesicles to the cis-Golgi compartment for further distribution by vesicular traffic or other mechanisms. We still know relatively little about what level of selectivity exists in packaging of membrane lipids into vesicular carriers, nor the precise quantitative contribution of vesicular versus non-vesicular transport. Another issue is the precise role of non-vesicular versus vesicular lipid traffic. Since practically all lipids can be efficiently exported by non-vesicular pathways, it is possible that the major role of non-vesicular transport is to maintain the proper lipid composition of each organelle, whereas COPII-dependent vesicular mechanism could be selective for specific lipids with particular biophysical or other properties, like very long chain ceramides, or lysophospholipids, that are required for protein sorting and concentration or specific membrane properties related to vesicle formation or fusion, such as those affecting coat protein recruitment, membrane bending rigidity or other properties. In this case, vesicular lipid transport would be essentially to serve as an enhancer of vesicular traffic of proteins. Examples of these types of lipid requirements have recently been seen in ER exit in yeast, but we do not know yet how pervasive these mechanisms will be. Finally, only a more complete and quantitative understanding of lipid traffic between the ER to other organelles of the secretory pathway will tell us more about whether and how the vesicular and non-vesicular pathways are coordinated. Transparency document The Transparency document associated this article can be found, in online version. Acknowledgements We thank Philipp Schlarmann for critical reading of this review. This work is supported by Japan Society for the Promotion of Science (JSPS), Grant-in-Aid for Scientific Research (KAKENHI) [JP16K07693 to K.F.], the NCCR Chemical Biology and the Swiss National Science 8

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