TM6SF2 acts at ER membrane contact sites to enable RAB7-dependent endolysosomal VLDL secretion and maintain Golgi structure.

Although a loss-of-function variant of TM6SF2 is a highly penetrant risk factor for steatotic liver disease, including progression to cirrhosis and cancer, its normal function is largely unknown. Here we show that endoplasmic reticulum (ER)-localized TM6SF2 forms membrane contact sites (MCSs) with late endosomes/lysosomes, where it activates the small GTPase RAB7 to enable an endolysosomal route for selective secretion of lipid-rich very low-density lipoprotein (VLDL) particles. In accord, TM6SF2 and RAB7 deficiency similarly cause endolysosomal VLDL retention and accumulation of enlarged late endosomes/lysosomes. TM6SF2 further binds to VAMP-associated protein (VAP) ER-anchor proteins to maintain MCSs between the ER, endosomes, and the trans-Golgi network, with TM6SF2 deficiency causing Golgi fragmentation and disruption of cGAS-STING signaling known to prevent cirrhosis and cancer by clearing senescent hepatocytes. Our findings establish TM6SF2 as an ER-MCS component that enables endolysosomal VLDL secretion and maintains Golgi structure, which suggests that TM6SF2 loss of function causes liver disease through steatosis-dependent and independent mechanisms.