2515256420945820 Reticulum–Lipid Droplet Nexus Journals.Sagepub.Com/Home/Ctc

Revisiting the Gregarious Lipid Droplet: Maintaining contacts to regulate energy homeostasis in the cell and beyond-Review Contact Volume 3: 1–16 Seipin-Mediated Contacts as Gatekeepers ! The Author(s) 2020 Article reuse guidelines: of Lipid Flux at the Endoplasmic sagepub.com/journals-permissions DOI: 10.1177/2515256420945820 Reticulum–Lipid Droplet Nexus journals.sagepub.com/home/ctc Veijo T. Salo1,2 , Maarit Holtt€ a-Vuori€ 1,2 and Elina Ikonen1,2 Abstract Lipid droplets (LDs) are dynamic cellular hubs of lipid metabolism. While LDs contact a plethora of organelles, they have the most intimate relationship with the endoplasmic reticulum (ER). Indeed, LDs are initially assembled at specialized ER subdomains, and recent work has unraveled an increasing array of proteins regulating ER-LD contacts. Among these, seipin, a highly conserved lipodystrophy protein critical for LD growth and adipogenesis, deserves special attention. Here, we review recent insights into the role of seipin in LD biogenesis and as a regulator of ER-LD contacts. These studies have also highlighted the evolving concept of ER and LDs as a functional continuum for lipid partitioning and pinpointed a role for seipin at the ER-LD nexus in controlling lipid flux between these compartments. Keywords seipin, endoplasmic reticulum–lipid droplet contacts, lipid droplet biogenesis Lipid droplets (LDs) are intracellular storage organelles mutations in seipin also result in hereditary spastic para- composed of a core of hydrophobic neutral lipids (NLs), plegias (Windpassinger et al., 2004) and a severe form of mainly triglycerides (TAG) and sterol esters, surrounded encephalopathy (Guillen-Navarro et al., 2013). Seipin is by a phospholipid (PL) monolayer (Henne et al., 2018). evolutionary conserved, and perturbation of seipin or its Their main function is to store excess energy in the form homologs results in aberrant LD morphology in numer- of TAGs, but LDs also play instrumental roles in many ous model systems (Szymanski et al., 2007; Fei et al., other cellular processes, including maintaining endoplas- 2008; Boutet et al., 2009; Cai et al., 2015; Salo et al., mic reticulum (ER) homeostasis (Welte, 2015; Olzmann 2016; Wang et al., 2016; Kornke and Maniak, 2017; and Carvalho, 2019). LDs are formed in the ER, and Coradetti et al., 2018; Cao et al., 2019). In accordance they retain a close physical and functional relationship with its role in lipodystrophy syndrome in humans, with it after their formation. The lipid and protein fluxes seipin is essential for adipogenesis in various organisms (Payne et al., 2008; Chen et al., 2009; Victoria et al., between these compartments are controlled at ER-LD 2010; Cui et al., 2011; Tian et al., 2011; Ebihara et al., contacts. Recent studies have begun to shed light on the 2015; Mori et al., 2016). properties of LD forming ER subdomains and ER-LD contacts. In this review, we discuss recent insights into LD biogenesis and ER-LD contacts with a special focus on the lipodystrophy protein seipin. 1Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki Seipin Structure Gives Clues to Its 2Minerva Foundation Institute for Medical Research, Helsinki, Finland Function Received April 7, 2020. Revised June 6, 2020. Accepted June 30, 2020. Seipin in an oligomeric ER transmembrane (TM) pro- Corresponding Author: tein originally identified to be mutated in Berardinelli– Elina Ikonen, Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Seip Congenital Lipodistrophy Type 2 (BSCL2) congen- Finland. ital lipodystrophy (Magre et al., 2001). Distinct Email: [email protected] Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en- us/nam/open-access-at-sage). 2 Contact The LD phenotype in the absence of seipin is consis- Structurally seipin contains two transmembrane tent among examined systems, with a proliferation of domains, an evolutionary conserved ER luminal loop tiny and some supersized LDs in an apparently stochas- and variable N- and C-terminal cytoplasmic regions tic manner (Cartwright and Goodman, 2012; Chen and (Lundin et al., 2006; Yang et al., 2013). The luminal Goodman, 2017). Several hypotheses have been pro- loop and its flanking two transmembrane domains are posed for seipin in relation to LDs: a role in controlling critical for seipin function in LD biogenesis, as they ER PL metabolism, sequestering NLs or regulating ER- alone are sufficient to rescue defective LD formation in LD contact sites. These hypotheses are not mutually seipin-deficient cells (Yang et al., 2013; Wang et al., exclusive, and the structure of seipin is in principle com- 2016). Seipin forms homo-oligomers, each containing patible with any of these. In addition to its role in LD 11 (human) or 12 (Drosophila) seipin monomers (Binns formation, seipin has been linked to cytoskeleton remod- et al., 2010; Sim et al., 2012; Sui et al., 2018; Yan et al., eling, calcium handling, and lipolysis (Chen et al., 2012; 2018). In yeast, seipin forms foci localizing to ER-LD Bi et al., 2014; Yang et al., 2014; Ding et al., 2018; Li contact sites (Szymanski et al., 2007; Fei et al., 2008). In et al., 2019b) with a growing number of identified inter- mammalian cells, endogenously fluorescently tagged action partners (Table 1). seipin appears as homogenous, discrete, and mobile foci in the ER, a subset of which are stably associated Table 1. Seipin Interacting Proteins. Proposed function Protein name Protein function Main evidence for interaction of interaction Reference Ldb16 Regulator of LD Co-ip: endogenous proteins in Forms a complex Cartwright et al. (2015), morphology yeast with seipin to Wang et al. (2014), and regulate LDs Wolinski et al. (2015) Promethin/LDAF1/ Regulator of LD iden- Co-ip: endogenous proteins Forms a complex Castro et al. (2019), Ldo45 Ldo16 tity (yeast) (yeast and human cells), with seipin to Chung et al. (2019), comigration of endogenously regulate LDs Eisenberg-Bord et al. tagged proteins (human cells) (2018), and Teixeira et al. (2018) GPAT3-4/Gat1-2 Catalyzes G3P to LPA Co-ip: endogenous proteins Seipin negatively Pagac et al. (2016) and Sim conversion (yeast), overexpressed pro- regulates GPAT et al. (2020) teins (murine cells) enzyme activity SERCA ER calcium pump, Co-ip: endogenous proteins Seipin positively Bi et al. (2014) þ transports Ca2 (human cells), overexpressed regulates SERCA into ER lumen proteins (Drosophila cells) activity Lipin-1 Catalyzes PA to DAG Co-ip and AFM: overexpressed Seipin recruits lipin Sim et al. (2012) and conversion proteins (murine cells) to the ER Talukder et al. (2015) membrane AGPAT-2 Catalyzes LPA to PA Co-ip and AFM: overexpressed Scaffolding of lipo- Sim et al. (2012) and conversion proteins (mice cells) genic enzymes Talukder et al. (2015) Serine palmitoyl- Sphingolipid synthesis Co-ip and BiFic of overexpressed Seipin negatively Su et al. (2019) transferase protein (yeast) regulates sphin- Complex, FA- golipid elongase Tsc13 production 14-3-3-b A scaffolding protein, Co-ip: overexpressed proteins Cytoskeleton Yang et al. (2014) signal transduction (murine and human cells) remodeling Perilipin-2 LD coat protein, lipol- Co-ip: overexpressed proteins Seipin regulates Mori et al. (2016) ysis regulator (human cells) perilipin-2 locali- zation to LDs Perilipin-1 LD coat protein, lipol- Co-ip and AFM: overexpressed Seipin regulates Jiao et al. (2019) ysis regulator proteins (human cells) perilipin-1 locali- zation to LDs Reep-1 Regulates ER Co-ip: overexpressed proteins None proposed Renvoise et al. (2016) morphology (murine cells) ER ¼ endoplasmic reticulum; AGPAT ¼ 1-acylglycerol-3-phosphate-O-acyltransferase; GPAT ¼ Glycerol-3-phosphate acyltransferase; SERCA ¼ sarco/ þ endoplasmic reticulum Ca2 -ATPase ; FA ¼ Fatty acid; G3P ¼ Glycerol 3-phosphate; LPA ¼Lysophosphatidic acid; DAG ¼ diacylglycerol; PA ¼ phosphatidic acid; LD ¼ lipid droplet; AFM ¼ Atomic force microscopy. Salo et al. 3 with ER-LD contacts (Salo et al., 2016; Wang et al., and Thiam, 2020), these seipin helices might recognize 2016). Seipin oligomerization is critical for its function, similar packing defects induced by NL lenses in the ER as evidenced by the fact that the lipodystrophy- (Sui et al., 2018). associated A212P-seipin mutant forms smaller The bulk of the seipin luminal region forms a beta- oligomers and fails to rescue the aberrant LD biogenesis sandwich-like fold, structurally similar to many lipid- of seipin-deficient cells (Binns et al., 2010; Sim et al., binding domains, including those of Niemann-Pick C2 2013; Salo et al., 2016). The same holds true for an olig- (NPC2) and PKC (Sui et al., 2018; Yan et al., 2018).This omerization deficient mutant designed based on the suggests that seipin may bind lipids in the ER lumen. In cryo-electron microscopy (EM) structure of seipin vitro work suggests that both purified full-length seipin (Yan et al., 2018). and a truncated variant containing only the putative The structures of the luminal domain of human and lipid binding domain can bind anionic PLs, such as Drosophila seipins have been solved by cryo-EM (Sui phosphatidic acid (PA; Sui et al., 2018). A mutant har- et al., 2018; Yan et al., 2018; Figure 1). They form a boring amino acid substitutions in the hydrophobic ring-like/disk-like structure of circa 15 nm in diameter, cavity of the beta sandwich was unable to complement with 11 (human) or 12 (Drosophila) seipin monomers the seipin knockout (KO) LD phenotype (Sui et al., closely intertwined. Each monomer displays two notable 2018). However, which lipids seipin interacts with in features: several hydrophobic helices (HHs) in very close intact cells remains to be determined.

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