mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a master regulator of metabolism and aging. A complex signaling network converges on mTORC1 and integrates growth factor, nutrient and stress signals. Aging is a dynamic process characterized by declining cellular survival, renewal, and fertility. Stressors elicited by aging hallmarks such as mitochondrial malfunction, loss of proteostasis, genomic instability and telomere shortening impinge on mTORC1 thereby contributing to age-related processes. Stress granules (SGs) constitute a cytoplasmic non-membranous compartment formed by RNA-protein aggregates, which control RNA metabolism, signaling, and survival under stress. Increasing evidence reveals complex crosstalk between the mTORC1 network and SGs. In this review, we cover stressors elicited by aging hallmarks that impinge on mTORC1 and SGs. We discuss their interplay, and we highlight possible links in the context of aging and age-related diseases.

Keywords: MTOR; aging hallmarks; amino acids; autophagy; cellular signaling; insulin; stress; stress granules (SGs).

FIGURE 1

The mTORC1 signaling network. mTORC1 is regulated by growth factors (insulin), amino acids and stressors. Insulin binds and activates the INSR, which recruits IRS and PI3Ks. PI3Ks convert PI4,5P2 to PI3,4,5P3 that serves as an anchor for PDPK1 and AKT1 at the plasma membrane. PDPK1 activates AKT1, which in turn inhibits AKT1S1 and the TSC complex. Hence, TSC-mediated RHEB inhibition is repressed resulting in mTORC1 activation at the lysosome. Amino acids regulate mTORC1 recruitment to the lysosomal surface mainly through the RRAG GTPases. mTORC1 phosphorylates many substrates including EIF4BP1, RPS6KB1 (S6K1) and GRB10. S6K1 and GRB10 mediate negative feedback loops towards the IRS and the INSR, respectively. Age-related stressors (depicted in red) activate or inhibit the mTORC1 network via different mechanisms. See main text for details and abbreviations.

FIGURE 2

Crosstalk between stress granules (SGs) and mTORC1 signaling. SG formation is triggered by EIF2S1 phosphorylation at serine 51 or at the level of the EIF4F complex. HRI/EIF2AK1, PKR/EIF2AK2, PERK/EIF2AK3 and GCN2/EIF2AK4 phosphorylate EIF2S1-S51 in response to different stresses. Under oxidative stress, also the mTORC1-S6Ks axis enhances phosphorylation of EIF2S1-S51. Upon Bortezomib (unfolded protein stress), SGs are induced by mTORC1-driven phosphorylation of EIF4EBP1 to sustain EIF4F complex assembly. PI3K and MAPK14 activate mTORC1 to promote SG formation. Autophagy is inhibited by mTORC1 and mediates SG clearance and composition. SGs inhibit mTORC1 by sequestration of MTOR and RPTOR and via the HSP90-DYRK3 axis. SGs also recruit TSC2 and S6K1 and 2 (S6Ks). See main text for details and abbreviations.