Sec14L6 is a PS and PI4P transporter that promotes lipid droplet formation

Lipid droplets (LDs) are evolutionarily conserved organelles that are crucial for cellular metabolism. LD biogenesis and growth occurs in the ER and requires the supply of phospholipid from the ER, but the molecular basis is largely unclear. Here, we have identified Sec14L6, a unique protein of the Sec14 family, as a PS/PI4P transporter required for LD biogenesis. Sec14L6 knockout (KO) greatly reduces the number of LDs that can be rescued by wild-type rather than lipid transfer-defective Sec14L6 mutants. We found that Sec14L6 directly interacts with ACSL3, and that this interaction facilitates targeting of Sec14L6 to LDs and activates the PS transfer activity of Sec14L6 in vitro. We also identified PGRMC1, an ER membrane protein, as an adaptor that recruits Sec14L6 to the ER. Furthermore, depletion of Sec14L6 impairs differentiation of adipose-derived mesenchymal stem cells. Together, our study suggests that Sec14L6 transports PS and/or PI4P between the ER and LDs to promote LD formation.