Let-7 coordinately suppresses components of the amino acid sensing pathway to repress mTORC1 and induce autophagy

TitleLet-7 coordinately suppresses components of the amino acid sensing pathway to repress mTORC1 and induce autophagy
Publication TypeJournal Article
Year of Publication2014
AuthorsDubinsky A.N, Dastidar S.G, Hsu C.L, Zahra R., Djakovic S.N, Duarte S., Esau C.C, Spencer B., Ashe T.D, Fischer K.M, MacKenna D.A, Sopher B.L, Masliah E., Gaasterland T., Chau B.N, de Almeida L.P, Morrison B.E, La Spada A.R
JournalCell Metabolism
Volume20
Pagination626-638
Date Published2014/10
Type of ArticleArticle
ISBN Number1550-4131
Accession NumberWOS:000343586500012
Keywordsactivation; disease; inhibition; metabolism; micrornas; mouse models; protein; rag gtpases; regulates mtor; tfeb
Abstract

Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway-the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 microRNA as capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately down-regulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain to eliminate protein aggregates, establishing its physiological relevance for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms.

DOI10.1016/j.cmet.2014.09.001
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