title: Let-7 coordinately suppresses components of the amino acid sensing pathway to repress mTORC1 and induce autophagy.
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 downregulating 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.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Dubinsky
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Somasish Ghosh
authors.initials: SG
authors.lastname: Dastidar
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Hsu
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Rabaab
authors.initials: R
authors.lastname: Zahra
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Stevan N
authors.initials: SN
authors.lastname: Djakovic
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal.
authors.forename: Sonia
authors.initials: S
authors.lastname: Duarte
authors.affiliation: Regulus Therapeutics, 3545 John Hopkins Court, Suite 210, San Diego, CA 92121, USA.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Esau
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Travis D
authors.initials: TD
authors.lastname: Ashe
authors.affiliation: Regulus Therapeutics, 3545 John Hopkins Court, Suite 210, San Diego, CA 92121, USA.
authors.forename: Kimberlee M
authors.initials: KM
authors.lastname: Fischer
authors.affiliation: Regulus Therapeutics, 3545 John Hopkins Court, Suite 210, San Diego, CA 92121, USA.
authors.forename: Deidre A
authors.initials: DA
authors.lastname: MacKenna
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Scripps Institute for Oceanography, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Gaasterland
authors.affiliation: Regulus Therapeutics, 3545 John Hopkins Court, Suite 210, San Diego, CA 92121, USA.
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Luis
authors.initials: L
authors.lastname: Pereira de Almeida
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Morrison
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Hospital, San Diego, CA 92123, USA. Electronic address: alaspada@ucsd.edu.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016415:Sequence Alignment; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D007328:Insulin; D035683:MicroRNAs; D046912:Multiprotein Complexes; C430723:RRAGD protein, human; C543044:MAP4K3 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins