Uncomplexed-TSC1 deploys novel mTORC1-independent pathway to exacerbate the liver glycogen storage in TSC.

ABSTRACT: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in TSC1 or TSC2 gene, leading to mTORC1 hyperactivation. However, mTORC1-independent mechanisms in this disorder remain poorly understood. In the study, excess glycogen storage was found in Tsc1^-/- cells, Tsc1^+/- and Tsc1^{c.2500-2503delAACA} mice, as well as in Tsc2^-/- cells, Tsc2^+/- and Tsc2^c.1113delA mice, with more pronounced accumulation in models with TSC2 defects. Mechanistically, the deficiency of TSC1 or TSC2 gene caused redundant uncomplexed-TSC2 or TSC1 protein, respectively. Strikingly, only uncomplexed-TSC1 downregulated the histone demethylase KDM5A, which in turn increased H3K4me3 levels at the METTL3 pr

SUBMITTER: Yue X 

PROVIDER: S-EPMC12618697 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature