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Identification of ER scramblases with crucial roles in lipid biology

Several recent papers have provided evidence that the DedA family proteins TMEM41B and VMP1 are ER-localized phospholipid scramblases. Phospholipid synthesis at the ER occurs at the cytosolic leaflet and therefore a scramblase that allows rapid, bidirectional flip-flop should be required to achieve balanced expansion of both leaflets.  These papers represent an important advance because a scramblase activity was found in ER membranes several decades ago but the proteins catalyzing this activity have been elusive.  In addition, TMEM41B and VMP1 were known to play an important roles in the production of autophagic membranes, lipoprotein secretion, regulation of lipid droplet formation, survival of neurons and as host factors for coronavirus and flavivirus infection. Papers from the Chen, Reinisch and Yang labs provide convincing biochemical evidence that the purified and reconstituted VMP1 and TMEM41B catalyze energy-independent flip-flop of phospholipid in proteoliposomes. Moreover, Huang et al. found that Tmem41b is required for lipoprotein production and lipid homeostasis in the mouse. Liver-specific inactivation of Tmem41b causes a substantial loss of plasma lipids and reduction of lipoprotein production in the ER. Lipids presumably bound for export by the hepatocytes are instead stored in cytosolic lipid droplets wrapped by distorted ER membranes, leading to a fatty liver and rapid progression to nonalcoholic steatohepatitis (NASH). This phenotype is exacerbated by the failure of these Tmem41b-deficient cells to properly downregulate SREBP to suppress sterol and lipid synthesis.  These ER scramblases appear to be acutely needed to support large fluxes of lipid from the ER membrane to either luminal structures in the case of lipoproteins, or cytosolic structures like lipid droplets and autophagosomes. In the latter process, Ghanbarpour et al. provide a compelling model for how a tandem protein array of the ER scramblase (TMEM41B and VMP1), a lipid transfer protein (ATG2) and an autophagosomal membrane scramblase (ATG9) collaborate to move phospholipid from the site of synthesis at the ER to the growing autophagosome membrane. The role of the scramblases is to provide balanced extraction of phospholipid from both leaflets of the ER, and balanced growth of both leaflets of the autophagosome. These papers provide an exciting new dimension in the study of membrane biogenesis.

TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis. Huang et al.

https://www.sciencedirect.com/science/article/pii/S1550413121002230?via%3Dihub

TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine. Li et al.

https://rupress.org/jcb/article/220/6/e202103105/212020/TMEM41B-and-VMP1-are-scramblases-and-regulate-the

A model for a partnership of lipid transfer proteins and scramblases in membrane expansion and organelle biogenesis. Ghanbarpour et al.

https://www.pnas.org/content/118/16/e2101562118


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2021