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Preprint WatchModerateJuly 30th, 2026

Structure and Function of TM6SF1 Reveal Role in mTORC1 Signaling

Hong, S.; Jia, L.; Wang, R.; Elghobashi-Meinhardt, N.; Hobbs, H. H.; Li, X.

TM6SF1 is a lysosomal cholesterol-binding protein that directly engages LAMTOR1 of the Ragulator complex in a cholesterol-dependent manner, and its loss perturbs mTORC1 signalling with reduced S6 kinase 1 and 4E-BP1 phosphorylation and constitutive TFEB activation.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Claidex holds one MTOR failure, everolimus with erlotinib in metastatic pancreatic cancer, terminated for futility and recorded as an efficacy failure (everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination). This preprint identifies a cholesterol-dependent lysosomal input to mTORC1 through TM6SF1 and LAMTOR1. An upstream regulator that gates mTORC1 activity through cholesterol availability implies that the pathway can be re-activated or buffered by lipid state independent of the kinase inhibitor, which is a plausible route to the limited activity recorded in everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination. The evidence is structural and cell-based with no disease model and no inhibitor combination tested, so it suggests a resistance hypothesis worth measuring rather than an established one.

Abstract excerpt

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 bulk lipidation of Apolipoprotein B-containing lipoproteins. Here we used cryo-electron microscopy (cryo-EM) to determine the structure of human TM6SF1 at 2.9 angstrom resolution. TM6SF1 forms a polytopic homodimer, with each protomer comprising ten transmembrane helices (TMs). TMs 1-6 form a pocket that accommodates a cholesterol molecule. Cell-based assays revealed that loss of TM6SF1 perturbs mTORC1 signaling, resulting in reduced phosphorylation of S6 kinase 1 and 4E-BP1 and constitutive activation of Transcription Factor EB (TFEB) and that cholesterol is required for these effects. Biochemical analyses support the model that TM6SF1 directly engages LAMTOR1, a component of Ragulator complex, in a cholesterol-dependent manner. Together, these findings identify TM6SF1 as a lysosomal cholesterol binding protein involved in regulating mTORC1 signaling.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.