Are endoplasmic reticulum subdomains shaped by asymmetric distribution of phospholipids? Evidence from a C. elegans model system

Abstract

Physical contact between organelles are widespread, in part to facilitate the shuttling of protein and lipid cargoes for cellular homeostasis. How do protein-protein and protein-lipid interactions shape organelle subdomains that constitute contact sites? The endoplasmic reticulum (ER) forms extensive contacts with multiple organelles, including lipid droplets (LDs) that are central to cellular fat storage and mobilization. Here, we focus on ER-LD contacts that are highlighted by the conserved protein seipin, which promotes LD biogenesis and expansion. Seipin is enriched in ER tubules that form cage-like structures around a subset of LDs. Such enrichment is strongly dependent on polyunsaturated and cyclopropane fatty acids. Based on these findings, we speculate on molecular events that lead to the formation of seipin-positive peri-LD cages in which protein movement is restricted. We hypothesize that asymmetric distribution of specific phospholipids distinguishes cage membrane tubules from the bulk ER.

A flexible network of lipid droplet associated proteins support embryonic integrity of C. elegans

“…FAT-3, a polyunsaturated fatty acyl (PUFA) desaturase, is required for targeting SEIP-1 to peri-LD cages in the intestine (Cao et al, 2019). We speculated that the PUFA products of FAT-3 may endow physical properties to ER tubules that are favorable for the recruitment of SEIP-1 to peri-LD cages (Cao et al, 2021). To this end, we asked if FAT-3 deficiency could modify the phenotypes of seip-1(-) worms.…”

Seipin collaborates with the ER membrane to control the sites of lipid droplet formation

“…In addition to membrane curvature, the structure of lipids and their asymmetric distribution at LD biogenesis sites can alter local surface tension and affect LD emergence [ 9 , 27 , 28 ]. Negative curvature inducing lipid, such as DAG, will stabilize the embedded state of LDs in the ER membrane, whereas lipids that induce positive curvature, such as lysophospholipids, reduce surface tension and promote emergence of small LDs both in vitro and in vivo [ 8 , 9 , 29 ].…”

A Unique Junctional Interface at Contact Sites Between the Endoplasmic Reticulum and Lipid Droplets

“…In addition, the directionality of LD emergence from the ER, i.e., whether LDs bud toward the cytoplasm or the ER lumen, is affected by an asymmetric distribution and packaging of lipids at LD biogenesis sites, surface tension, membrane curvature properties, and lateral pressure (Chorlay et al, 2019;Gao et al, 2019). Even the acyl composition on ER phospholipids affects LD formation as lipids containing short chain and saturated fatty acids antagonize LD formation and instead promote NL accumulation in the ER (Hashidate-Yoshida et al, 2015;Cao et al, 2021;Zoni et al, 2021). In vitro studies with model membranes indicate that a reduction in surface tension through the accumulation of lysophospholipids promotes budding of small LDs (Ben M'barek et al, 2017).…”