Regulation of autophagy and survival in response to metabolic stress by p27/Kip1
Conference of Arnaud Besson of the CBI of Toulouse on Friday March 05, 2021 within the framework of the Scientific Animation Committee -CAS-.
Autophagy is a catabolic process whereby cytoplasmic components are degraded within lysosomes, allowing cells to maintain energy homeostasis during nutrient depletion. Several studies reported that the CDK inhibitor p27Kip1 promotes starvation-induced autophagy by a still unknown mechanism. We found that p27 regulates autophagy by distinct mechanisms in response to different metabolic stress. Likewise, p27 status differentially affects cell survival in response to amino acid or glucose starvation.
In response to glucose deprivation, p27 promotes autophagy by facilitating autophagosome trafficking along microtubule tracks by increasing microtubule acetylation via an α-tubulin acetyltransferase (ATAT1)-dependent mechanism. We find that p27 promotes microtubule acetylation by binding to and stabilizing ATAT1.
In contrast, in amino acid deprived cells, p27 controls autophagy via an mTORC1-dependent mechanism. During prolonged starvation, a fraction of p27 is recruited to lysosomes where it interacts with LAMTOR1, a component of the Ragulator complex required for mTORC1 activation. p27 binding to LAMTOR1 prevents Ragulator assembly and mTORC1 activation, promoting autophagy. Conversely, p27-/- cells exhibit elevated mTORC1 signaling, and impaired lysosomal activity and autophagy. This is associated with cytoplasmic sequestration of TFEB, preventing induction of lysosomal genes required for lysosome function. LAMTOR1 silencing or mTOR inhibition restores autophagy and induces apoptosis in p27-/- cells. Thus, these results reveal a direct, coordinated regulation between the cell cycle and cell growth machineries, and that p27 may serve to maintain growth inhibition in conditions of sustained metabolic stress.
05 march 2021
Conference 54 minutes and 56 secondes
Toulouse Cancer Research Center (Oncopole)
Toulouse – FR
+33 5 82 74 15 75
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