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TMEM41B and VMP1, two endoplasmic reticulum (ER)-resident transmembrane proteins, play important roles in regulating the formation of lipid droplets (LDs), autophagy initiation, and viral infection. However, the biochemical functions of TMEM41B and VMP1 are unclear. A lipids distribution screen suggested TMEM41B and VMP1 are critical to the normal distribution of cholesterol and phosphatidylserine. Biochemical analyses unveiled that TMEM41B and VMP1 have scramblase activity. These findings shed light on the mechanism by which TMEM41B and VMP1 regulate LD formation, lipids distribution, macroautophagy, and viral infection.

VMP1 and TMEM41B, integral membrane proteins of the ER, regulate the formation of autophagosomes, lipid droplets, and lipoproteins. Here, Li, Wang, et al. show that they have phospholipid scramblase activity, which is essential to the normal distribution of cholesterol and phosphatidylserine in mammalian cells., TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins. Recently, TMEM41B was identified as a crucial host factor for infection by all coronaviruses and flaviviruses. The molecular function of TMEM41B and VMP1, which belong to a large evolutionarily conserved family, remains elusive. Here, we show that TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. Their mechanism of action on LD formation is likely to be different from that of seipin. Their role in maintaining cellular phosphatidylserine and cholesterol homeostasis may partially explain their requirement for viral infection. Our results suggest that the proper sorting and distribution of cellular lipids are essential for organelle biogenesis and viral infection.