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

TM6SF2 at ER membrane contact sites activates RAB7 to enable endolysosomal VLDL secretion and maintains Golgi structure in liver cells.

• Why it matters: Understanding TM6SF2's function is crucial because its loss-of-function variant is a significant risk factor for steatotic liver disease, cirrhosis, and cancer, yet its normal role was largely unknown.
• What they did: The study used cellular models to show that TM6SF2 forms membrane contact sites with late endosomes/lysosomes, activates RAB7, and interacts with VAP proteins; deficiency causes VLDL retention, enlarged endosomes/lysosomes, Golgi fragmentation, and disrupted cGAS-STING signaling.
• The result: Findings suggest that TM6SF2 loss of function may promote liver disease through mechanisms involving impaired VLDL secretion and Golgi disruption, impacting disease progression and potential therapeutic targets.