Tsc1 regulates tight junction independent of mTORC1

Abstract

Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor that functions together with Tsc2 to negatively regulate the mechanistic target of rapamycin complex 1 (mTORC1) activity. Here, we show that Tsc1 has a critical role in the tight junction (TJ) formation of epithelium, independent of its role in Tsc2 and mTORC1 regulation. When an epithelial cell establishes contact with neighboring cells, Tsc1, but not Tsc2, migrates from the cytoplasm to junctional membranes, in which it binds myosin 6 to anchor the perijunctional actin cytoskeleton to β-catenin and ZO-1. In its absence, perijunctional actin cytoskeleton fails to form. In mice, intestine-specific or inducible, whole-body Tsc1 ablation disrupts adherens junction/TJ structures in intestine or skin epithelia, respectively, causing Crohn’s disease–like symptoms in the intestine or psoriasis-like phenotypes on the skin. In patients with Crohn’s disease or psoriasis, junctional Tsc1 levels in epithelial tissues are markedly reduced, concomitant with the TJ structure impairment, suggesting that Tsc1 deficiency may underlie TJ-related diseases. These findings establish an essential role of Tsc1 in the formation of cell junctions and underpin its association with TJ-related human diseases.

mTORC1 Activity in Psoriatic Lesions Is Mediated by Aberrant Regulation through the Tuberous Sclerosis Complex

“…Ablation of TSC1 in mice disrupts TJs and causes a psoriasis-like phenotype. At the same time, junctional TSC1 was markedly reduced in psoriatic skin, suggesting that TSC1 deficiencies underlies epidermal barrier deficiencies due to TJ impairment [ 46 ].…”

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

“…TSC1 −/− and TSC2 −/− MEFs demonstrate rapamycin insensitive increase in number and length of cilia [ 85 ] whereas only Tsc2 loss promotes an mTOR-dependent pro-migratory phenotype [ 86 ]. On the other hand, Tsc1 loss was shown to dysregulate tight junction development in an mTOR independent manner [ 87 ]. Collectively, these studies suggest a role for Tsc1 in cell integrity independent of mTOR.…”

Arginine depletion attenuates renal cystogenesis in tuberous sclerosis complex model

“… 17 , 18 , 19 , 20 Moreover, Tsc1 was shown to control tight junction formation to create and maintain the epithelial barrier by mTORC1-independent pathways. 21 Tsc1 hemizygous deletion in NPCs had mTOR-independent effects on nephrogenesis. 22 Tsc2 deletion affected prostaglandin production, NOTCH activity, and VEGF gene expression in a mTORC1-independent mechanism.…”