RESUMO
The nutrient-activated mTORC1 (mechanistic target of rapamycin kinase complex 1) signaling pathway determines cell size by controlling mRNA translation, ribosome biogenesis, protein synthesis, and autophagy. Here, we show that vimentin, a cytoskeletal intermediate filament protein that we have known to be important for wound healing and cancer progression, determines cell size through mTORC1 signaling, an effect that is also manifested at the organism level in mice. This vimentin-mediated regulation is manifested at all levels of mTOR downstream target activation and protein synthesis. We found that vimentin maintains normal cell size by supporting mTORC1 translocation and activation by regulating the activity of amino acid sensing Rag GTPase. We also show that vimentin inhibits the autophagic flux in the absence of growth factors and/or critical nutrients, demonstrating growth factor-independent inhibition of autophagy at the level of mTORC1. Our findings establish that vimentin couples cell size and autophagy through modulating Rag GTPase activity of the mTORC1 signaling pathway.
Assuntos
Filamentos Intermediários , Complexos Multiproteicos , Animais , Autofagia/fisiologia , Tamanho Celular , GTP Fosfo-Hidrolases/metabolismo , Filamentos Intermediários/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Complexos Multiproteicos/metabolismo , Transdução de Sinais , Vimentina/metabolismoRESUMO
As a member of the large family of intermediate filaments (IFs), vimentin has emerged as a highly dynamic and versatile cytoskeletal protein involved in many key processes of wound healing. It is well established that vimentin is involved in epithelial-mesenchymal transition (EMT) during wound healing and metastasis, during which epithelial cells acquire more dynamic and motile characteristics. Moreover, vimentin participates in multiple cellular activities supporting growth, proliferation, migration, cell survival, and stress resilience. Here, we explore the role of vimentin at each phase of wound healing, with focus on how it integrates different signaling pathways and protects cells in the fluctuating and challenging environments that characterize a healing tissue.