Elucidating a mechanism of mTORC1 activation independent of amino acids signaling

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DESCRIPTION (provided by applicant): The mechanisms underlying the pro-aging consequences of mTOR activity are obscure. Deregulated mTOR activity leads to accelerated aging and upregulated mTORC1 activity occurs in aging organisms. We recently described the Rag family of proteins as key for mTORC1 activation by amino acids, through a mechanism that requires mTORC1 shuttling to the lysosomal surface. We have generated a series of immortalized cell lines derived from genetically-engineered mice that lack the RagA gene. Although mTORC1 activity is barely detectable in RagA-deficient embryos, cell lines derived from them have reactivated mTORC1 signaling, which is now insensitive to amino acids withdrawal, but sensitive to growth factors withdrawal. Intriguingly, in these lines mTORC1, although active, does not localize to lysosomes, indicating that an additional unknown mechanism of mTORC1 activation is at work. Based on a combination of transcriptional profiling and proteomic-based approaches, we plan to find the genes responsible for the lysosomal-independent activation of mTORC1 and to understand how this occurs. We will then take advantage of RagA-null livers to study in vivo the consequences of altering the expression of the candidates found. Further elucidation of the molecular mechanism leading to mTORC1 desensitization to amino acid withdrawal, together with the identification of druggable targets within this pathway, may pave the way for novel therapeutic approaches to aging and age-related diseases.