Transport Pathways That Contribute to the Cellular Distribution of Phosphatidylserine

Abstract

Phosphatidylserine (PS) is a negatively charged phospholipid that displays a highly uneven distribution within cellular membranes, essential for establishment of cell polarity and other processes. In this review, we discuss how combined action of PS biosynthesis enzymes in the endoplasmic reticulum (ER), lipid transfer proteins (LTPs) acting within membrane contact sites (MCS) between the ER and other compartments, and lipid flippases and scramblases that mediate PS flip-flop between membrane leaflets controls the cellular distribution of PS. Enrichment of PS in specific compartments, in particular in the cytosolic leaflet of the plasma membrane (PM), requires input of energy, which can be supplied in the form of ATP or by phosphoinositides. Conversely, coupling between PS synthesis or degradation, PS flip-flop and PS transfer may enable PS transfer by passive flow. Such scenario is best documented by recent work on the formation of autophagosomes. The existence of lateral PS nanodomains, which is well-documented in the case of the PM and postulated for other compartments, can change the steepness or direction of PS gradients between compartments. Improvements in cellular imaging of lipids and membranes, lipidomic analysis of complex cellular samples, reconstitution of cellular lipid transport reactions and high-resolution structural data have greatly increased our understanding of cellular PS homeostasis. Our review also highlights how budding yeast has been instrumental for our understanding of the organization and transport of PS in cells.

The Integrated Analysis of Transcriptomics and Metabolomics Unveils the Therapeutical Effect of Asiatic Acid on Alcoholic Hepatitis in Rats

“…Besides, PC and PE are important supporting nutrients for the liver, exert an obvious protective effect against liver damage from viruses, pharmaceuticals, alcoholism, and other toxic in uences [36,38]. Phosphatidylserine (PS) is a glycerol phospholipid with negatively charged head groups [39]. In this study, the analysis revealed 480 differential metabolites between the AA and model groups, which were largely enriched in the lipid-related metabolic pathways, and glycerophospholipid metabolism was the most relevant pathway.…”

Scramblases as Regulators of Proteolytic ADAM Function

“…Diverse transmembrane proteins have been implicated in lipid scrambling. Members of the TMEM16 family are by far the best characterized [41,42].…”

Mechanisms of Non-Vesicular Exchange of Lipids at Membrane Contact Sites: Of Shuttles, Tunnels and, Funnels

“…Technically they are not considered as lipid “transfer” proteins as they do not shuttle lipids across an aqueous space between membranes. Their functional importance is considerable as they abolish (i.e., scramblases) or establish (i.e., flippases and floppases) membrane asymmetry and contribute to lipid fluxes (in particular PS) at MCSs and within the cell through the formation of gradients between leaflets within a membrane and thus support the formation of lateral nanodomains not only within the membrane but also within leaflets ( Shin and Takatsu, 2020 ; Lenoir et al, 2021 ) ( Figures 12A,B ). Flippases transport lipids (sterols, glycerophospholipids such as PS, PE or PC and ceramides) from the exoplasmic (external or luminal) to the cytoplasmic leaflet while floppases work in the opposite direction; these processes require ATP hydrolysis to enable the vectorial transport against a concentration gradient.…”

“…Scramblases equilibrate lipid distributions between leaflets and thus dissipate lipid asymmetry in membranes; they are ATP-independent and follow energy potential gradients associated with a simple chemical concentration gradient or the membrane electric potential (resulting from charge distributions) ( Lenoir et al, 2021 ). The first scramblase structure belongs to the TMEM16 protein family ( Brunner et al, 2014 ; Brunner et al, 2016 ) and reveals a dimer where each monomer bears a membrane-spanning hydrophilic cleft facing the lipid environment.…”

“…Organelle membranes have very distinct lipid compositions ( van Meer et al, 2008 ) as a result of the compartmentalization of lipid biosynthetic pathways and of vesicular and non-vesicular trafficking. Furthermore, membranes are asymmetrical and heterogenous: Integral membrane proteins known as lipid scramblases and lipid flippases/floppases affect the repartition of lipids (in particular PS) between leaflets and the creation of lipidic micro or nanodomains ( Montigny et al, 2016 ; Shin and Takatsu, 2020 ; Lenoir et al, 2021 ). The creation and maintenance of lipid fluxes and gradients and the resulting membrane asymmetry are essential to the establishment of organelle identity and a functional organelle network.…”