The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back.

Ulrike Rehbein,Kathrin Thedieck,Alexander Martin Heberle,Mirja Tamara Prentzell,Elizabeth P Henske,Marti Cadena Sandoval,Christiane A Opitz

doi:10.3389/fcell.2021.751892

Abstract

The tuberous sclerosis protein complex (TSC complex) is a key integrator of metabolic signals and cellular stress. In response to nutrient shortage and stresses, the TSC complex inhibits the mechanistic target of rapamycin complex 1 (mTORC1) at the lysosomes. mTORC1 is also inhibited by stress granules (SGs), RNA-protein assemblies that dissociate mTORC1. The mechanisms of lysosome and SG recruitment of mTORC1 are well studied. In contrast, molecular details on lysosomal recruitment of the TSC complex have emerged only recently. The TSC complex subunit 1 (TSC1) binds lysosomes via phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]. The SG assembly factors 1 and 2 (G3BP1/2) have an unexpected lysosomal function in recruiting TSC2 when SGs are absent. In addition, high density lipoprotein binding protein (HDLBP, also named Vigilin) recruits TSC2 to SGs under stress. In this mini-review, we integrate the molecular mechanisms of lysosome and SG recruitment of the TSC complex. We discuss their interplay in the context of cell proliferation and migration in cancer and in the clinical manifestations of tuberous sclerosis complex disease (TSC) and lymphangioleiomyomatosis (LAM).

Highlights

For cellular growth and survival, cells have to tightly balance their metabolism to adapt to nutritional changes and environmental stressors
Growth factor and nutrient sufficiency reduce the amount of lysosomal tuberous sclerosis complex disease (TSC) complex (Demetriades et al, 2014; Menon et al, 2014; Carroll et al, 2016), increasing the abundance of RHEB-GTP and activating mechanistic target of rapamycin complex 1 (mTORC1) (Zhang et al, 2003; Menon et al, 2014)
To G3BPs, the RHEB and RRAG GTPases contribute to the lysosomal recruitment of the TSC complex (Demetriades et al, 2014; Menon et al, 2014; Carroll et al, 2016; Yang et al, 2020)

Summary

Introduction

For cellular growth and survival, cells have to tightly balance their metabolism to adapt to nutritional changes and environmental stressors. The Lysosomal TSC Complex and SGs Inhibit mTORC1 The TSC complex integrates signals from multiple growth factor pathways (Huang and Manning, 2008), as well as nutrient sufficiency and cellular stresses (Demetriades et al, 2014, 2016; Menon et al, 2014; Plescher et al, 2015; Carroll et al, 2016).

Results

Conclusion