TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis

Genome-scale CRISPR screen identifies TMEM41B as a multi-function host factor required for coronavirus replication

“…In addition, the serum lipid concentrations, including those of triglyceride, total cholesterol, and low-density lipoprotein cholesterol, in the serum of TMEM41B +/− mice decreased significantly compared with those in WT mice ( S13H Fig ). The results indicated that TMEM41B +/− mice may have defective on lipid transport, which is consistent with a previous study [ 55 ].…”

“…Two sgRNAs were employed to delete the region spanning Exons 2 to 5 of the TMEM41B gene (S13A Fig) . However, consistent with other studies reporting TMEM41B as an essential component for mouse embryonic development [54], we were only able to obtain heterozygous TMEM41B KO mice (S13B-S13E Fig) . In heterozygous KO mice (TMEM41B +/− ), the TMEM41B mRNA levels were reduced by approximately 60% in liver tissue (S13F Fig) . The impairment of autophagic flux characterized by p62 accumulation was significantly increased in the liver and kidney of TMEM41B +/− mice compared with that in WT mice. This result suggested that autophagic activity was disturbed in TMEM41B +/− mice (S13G Fig) . In addition, the serum lipid concentrations, including those of triglyceride, total cholesterol, and low-density lipoprotein cholesterol, in the serum of TMEM41B +/− mice decreased significantly compared with those in WT mice (S13H Fig) . The results indicated that TMEM41B +/− mice may have defective on lipid transport, which is consistent with a previous study [55].…”

Perspectives on Mitochondria–ER and Mitochondria–Lipid Droplet Contact in Hepatocytes and Hepatic Lipid Metabolism

“…Vacuole membrane protein 1 (VMP1) and transmembrane protein 41B (TMEM41B) are both ER transmembrane proteins, which play critical roles in LD biogenesis, VLDL assembly and secretion and regulating the formation and closure of autophagosomes [51][52][53]. Recent evidence indicates that both VMP1 and TMEM41B, as well as ATG9, have lipid scramblase activity that regulate the shuttle of phospholipids across the membrane-lipid bilayer [54][55][56], which may promote autophagosome membrane expansion and eventual formation. In addition to regulating autophagosome formation, VMP1 also regulates organelle contacts, including ER-mitochondrial and ER-autophagosome contact [57,58]; though whether VMP1-mediated ER-mitochondrial contact contributes to VLDL assembly and secretion remains unknown.…”

“…In addition to regulating autophagosome formation, VMP1 also regulates organelle contacts, including ER-mitochondrial and ER-autophagosome contact [57,58]; though whether VMP1-mediated ER-mitochondrial contact contributes to VLDL assembly and secretion remains unknown. The loss of hepatic TMEM41B in mice results in severe hepatic steatosis due to impaired VLDL secretion and increased de novo lipogenesis, revealing the crucial role of the protein in these cellular pathways [54].…”

Flavivirus–host interactions: an expanding network of proviral and antiviral factors

“…Growing evidence indicates that TMEM41B and a related protein, VMP1, act at the early stages of autophagosome formation, possibly mobilizing lipids in the ER to facilitate membrane curvature [ 14 , 15 • , 16 , 17 , 45 , 46 ]. Indeed, several groups have shown that both proteins act as phospholipid scramblases capable of flipping lipids between leaflets of lipid bilayers [ 47 , 48 • , 49 , 50 , 51 ]. It is possible that flaviviruses and coronaviruses hijack this function to form ROs on ER membranes by recruiting one or both proteins through direct protein–protein interaction.…”