Preprint: Cholesterol-dependent lysosomal docking of mTORC1 mediated by TM6SF1

WHY IT MATTERS

This basic research identifies TM6SF1's function for the first time, which could eventually lead to targeted treatments for genetic disorders caused by TM6SF1 mutations or diseases involving mTORC1 dysregulation like tuberous sclerosis or certain cancers.

Scientists discovered that a protein called TM6SF1 sits on the surface of lysosomes (tiny compartments inside cells that break down waste) and helps control a cellular growth regulator called mTORC1. When TM6SF1 is missing, mTORC1 stays constantly active instead of being properly regulated. This finding helps explain what TM6SF1 does in the body and could eventually lead to new treatments for diseases where this protein or pathway goes wrong.

Cholesterol-dependent lysosomal docking of mTORC1 mediated by TM6SF1 Authors: Hong, S. et al. Server: bioRxiv Category: cell biology Abstract: The Transmembrane 6 Superfamily (TM6SF) comprises two members: TM6SF1, a ubiquitously expressed lysosomal membrane protein of unknown function, and TM6SF2, an endoplasmic reticulum protein required for lipidation of Apolipoprotein B-containing lipoproteins. Here, we identify TM6SF1 as a cholesterol-bound lysosomal docking factor for mTORC1. Loss of TM6SF1 disrupts spatial organization of the lysosomal mTORC1 machinery and results in constitutive activation of Transcription Factor EB (TFEB) without altering lysosomal pH or interfering with cholesterol trafficking. Using cryo-electron microscopy