Lipid topogenesis — 35 years on

Abstract

Glycerophospholipids are the principal fabric of cellular membranes. The pathways by which these lipids are synthesized were elucidated mainly through the work of Kennedy and colleagues in the late 1950s and early 1960s. Subsequently, attention turned to cell biological aspects of lipids: Where in the cell are lipids synthesized? How are lipids integrated into membranes to form a bilayer? How are they sorted and transported from their site of synthesis to other cellular destinations? These topics, collectively termed ‘lipid topogenesis’, were the subject of a review article in 1981 by Bell, Ballas and Coleman. We now assess what has been learned about early events of lipid topogenesis, i.e. “lipid synthesis, the integration of lipids into membranes, and lipid translocation across membranes”, in the 35 years since the publication of this important review. We highlight the recent elucidation of the X-ray structures of key membrane enzymes of glycerophospholipid synthesis, progress on identifying lipid scramblase proteins needed to equilibrate lipids across membranes, and new complexities in the subcellular location and membrane topology of phosphatidylinositol synthesis revealed through a comparison of two unicellular model eukaryotes.

Lipid somersaults: Uncovering the mechanisms of protein-mediated lipid flipping

“…Biogenic membranes, such as the endoplasmic reticulum (ER) and bacterial cytoplasmic membrane (bCM), are capable of such self-synthesis. Lipid synthesis is asymmetric such that newly formed lipids are deposited in the cytoplasmic leaflet of the ER or bCM [29]. For bilayer formation, new lipids must be moved to the opposite leaflet on a physiologically relevant time frame.…”

Scrambling of natural and fluorescently tagged phosphatidylinositol by reconstituted G protein–coupled receptor and TMEM16 scramblases

“…Glycerophospholipids are essential components of all eukaryotic membranes. The most abundant classes, phosphatidylcholine (PC) 3 and phosphatidylethanolamine (PE), are synthesized via the Kennedy pathways (1) on the cytoplasmic face of the endoplasmic reticulum (ER) (2)(3)(4)(5)(6)(7). There are no parallel pathways to synthesize phospholipids in the luminal leaflet of the ER.…”

Osh6 requires Ist2 for localization to the ER-PM contacts and efficient phosphatidylserine transport

“…Finally, it is intriguing that the membrane-embedded portion of Ist2 bears structural homology to the mammalian TMEM16 family of proteins, which function as Ca 2+ -activated lipid scramblases and/or ion channels in the PM or in the ER (Falzone et al, 2018;Bushell et al, 2019). Since PS is synthesized exclusively on the cytosolic side of the ER (Chauhan et al, 2016), lipid scrambling would be another way to regulate the size of the PS pool available for transport by a cytosolic LTP. When reconstituted into liposomes, Ist2 did not display any lipid scramblase activity (Malvezzi et al, 2013).…”