Promethin Is a Conserved Seipin Partner Protein

Castro, Inês G.; Eisenberg-Bord, Michal; Persiani, Elisa; Rochford, Justin J.; Schuldiner, Maya; Bohnert, Maria

doi:10.3390/cells8030268

Cited by 58 publications

(52 citation statements)

References 44 publications

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“…In addition, members of the vacuolar protein sortingassociated protein 13 (Vps13) family have been shown to be involved in ER-LD contacts, possibly to mediate lipid transfer (Kumar et al, 2018); however, whether Vps13 has a partner on LDs has not yet been resolved. Seipin protein partners have been proposed to participate in the interactions of LDs; these include promethin in mammals (Castro et al, 2019), Ldo proteins in yeast (Teixeira et al, 2018;Eisenberg-Bord et al, 2018) and the LDAP proteins in Arabidopsis. Importantly, all these proteins have key roles in LDs biogenesis.…”

Section: Heterotypic or Homotypic Protein Dimerizationmentioning

confidence: 99%

Lipid droplet–membrane contact sites – from protein binding to function

Thiam

Dugail

2019

Journal of Cell Science

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In the general context of an increasing prevalence of obesityassociated diseases, which follows changing paradigms in food consumption and worldwide use of industry-transformed foodstuffs, much attention has been given to the consequences of excessive fattening on health. Highly related to this clinical problem, studies at the cellular and molecular level are focused on the fundamental mechanism of lipid handling in dedicated lipid droplet (LD) organelles. This Review briefly summarizes how views on LD functions have evolved from those of a specialized intracellular compartment dedicated to lipid storage to exerting a more generalized role in the stress response. We focus on the current understanding of how proteins bind to LDs and determine their function, and on the new paradigms that have emerged from the discoveries of the multiple contact sites formed by LDs. We argue that elucidating the important roles of LD tethering to other cellular organelles allows for a better understanding of LD diversity and dynamics.

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Section: Heterotypic or Homotypic Protein Dimerizationmentioning

confidence: 99%

Lipid droplet–membrane contact sites – from protein binding to function

Thiam

Dugail

2019

Journal of Cell Science

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“…In addition to GPATs, AGPAT2 and lipins, a range of other proteins have been identified as seipin interacting partners that may regulate lipid droplets in multiple cell types and species. These include ADRP, SERCA2A, 14-3-3β, perilipin, promethin and Reep1 in mammalian cells [17][18][19][36][37][38][39][40][41] and Pet10p, Ldo45 and Ldo16 in yeast [42][43][44] . In addition, two groups have recently reported the structure of seipin homo-oligomers determined by cryo-EM.…”

Section: Discussionmentioning

confidence: 99%

Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation

Sim

Persiani

Talukder

et al. 2020

Sci Rep

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Seipin deficiency causes severe congenital generalized lipodystrophy (CGL) and metabolic disease. However, how seipin regulates adipocyte development and function remains incompletely understood. We previously showed that seipin acts as a scaffold protein for AGPAT2, whose disruption also causes CGL. More recently, seipin has been reported to promote adipogenesis by directly inhibiting GPAT3, leading to the suggestion that GPAT inhibitors could offer novel treatments for CGL. Here we investigated the interactions between seipin, GPAT3 and AGPAT2. We reveal that seipin and GPAT3 associate via direct interaction and that seipin can simultaneously bind GPAT3 and AGPAT2. Inhibiting the expression of seipin, AGPAT2 or GPAT3 led to impaired induction of early markers of adipocyte differentiation in cultured cells. However, consistent with normal adipose mass in GPAT3null mice, GPAT3 inhibition did not prevent the formation of mature adipocytes. Nonetheless, loss of GPAT3 in seipin-deficient preadipocytes exacerbated the failure of adipogenesis in these cells. Thus, our data indicate that GPAT3 plays a modest positive role in adipogenesis and argue against the potential of GPAT inhibitors to rescue white adipose tissue mass in CGL2. Overall, our study reveals novel mechanistic insights regarding the molecular pathogenesis of severe lipodystrophy caused by mutations in either seipin or AGPAT2.

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“…But would the continuity of this hemimembrane also allow integral membrane proteins to move between an ER bilayer and an LD monolayer? This may be an option for dedicated proteins, such as possibly LDAF1/Promethin, a polytopic membrane protein which is closely associated with seipin and relocates from the ER to the LD surface upon maturation of LDs (Castro et al, 2019;Chung et al, 2019) }. On the other hand, for non-dedicated ER residential membrane proteins as used in this study, i.e., Sec61 and Wbp1, it is difficult to imagine how they could relocate from a bilayer environment to the limiting membrane of LDs.…”

Section: Discussionmentioning

confidence: 99%

The surface of lipid droplets constitutes a barrier for endoplasmic reticulum residential integral membrane spanning proteins

Khaddaj

Mari

Cottier

et al. 2020

Preprint

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Lipid droplets (LDs) constitute globular subcellular structures that mainly serve to store energy in form of neutral lipids, particularly triacylglycerol and steryl esters. LDs are closely associated with the membrane of the endoplasmic reticulum (ER), and are limited by a monolayer membrane of phospholipids harboring a specific set of proteins. Most of these proteins associate with LDs through either an amphipathic helix or a membrane-embedded hairpin motif. Here we address the question whether integral membrane proteins could localize to the surface of LDs. To test this, we fused perilipin 3 (PLIN3), a mammalian LD-targeted protein, to ER resident proteins, such as Wbp1 (a N-glycosyl transferase complex subunit), Sec61 (a translocon subunit), and Pmt1 (a protein O-mannosyltransferase). The resulting fusion proteins localize to the rim of LDs in both yeast and mammalian cells. LD targeting of membrane proteins is not only observed with the PLIN3-containing fusion proteins, but also for native endogenous polytopic transmembrane proteins. These data indicate that integral membrane proteins that function in a bilayer membrane can reversibly associate with the LD surface, suggesting that the LD surface is continuous with the ER membrane. In cells lacking LDs, Wbp1 and Sec61 fusion proteins localize to the ER, forming crescent-like membrane protrusions. These ER crescents resemble sites of LD formation as they contain seipin and other LD-localized proteins, suggesting that membrane-anchored PLIN3 induces the formation of membrane subdomains.

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Promethin Is a Conserved Seipin Partner Protein

Cited by 58 publications

References 44 publications

Lipid droplet–membrane contact sites – from protein binding to function

Lipid droplet–membrane contact sites – from protein binding to function

Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation

The surface of lipid droplets constitutes a barrier for endoplasmic reticulum residential integral membrane spanning proteins

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