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

Amy N Dubinsky; Somasish Ghosh Dastidar; Cynthia L Hsu; Rabaab Zahra; Stevan N Djakovic; Sonia Duarte; Christine C Esau; Brian Spencer; Travis D Ashe; Kimberlee M Fischer; Deidre A MacKenna; Bryce L Sopher; Eliezer Masliah; Terry Gaasterland; B Nelson Chau; Luis Pereira de Almeida; Bradley E Morrison; Albert R La Spada

doi:10.1016/j.cmet.2014.09.001

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

Cell Metab. 2014 Oct 7;20(4):626-38. doi: 10.1016/j.cmet.2014.09.001.

Authors

Amy N Dubinsky¹, Somasish Ghosh Dastidar¹, Cynthia L Hsu¹, Rabaab Zahra¹, Stevan N Djakovic¹, Sonia Duarte², Christine C Esau³, Brian Spencer⁴, Travis D Ashe¹, Kimberlee M Fischer³, Deidre A MacKenna³, Bryce L Sopher⁵, Eliezer Masliah⁴, Terry Gaasterland⁶, B Nelson Chau³, Luis Pereira de Almeida⁷, Bradley E Morrison¹, Albert R La Spada⁸

Affiliations

¹ Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
² CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal.
³ Regulus Therapeutics, 3545 John Hopkins Court, Suite 210, San Diego, CA 92121, USA.
⁴ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Department of Neurology, University of Washington, Seattle, WA 98195, USA.
⁶ 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.
⁷ 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.
⁸ 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue, White / metabolism
Amino Acids / metabolism*
Animals
Autophagy*
Base Sequence
Brain / metabolism
Cells, Cultured
HEK293 Cells
Humans
Insulin / metabolism
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Inbred C57BL
Mice, Transgenic
MicroRNAs / antagonists & inhibitors
MicroRNAs / metabolism*
Monomeric GTP-Binding Proteins / antagonists & inhibitors
Monomeric GTP-Binding Proteins / genetics
Monomeric GTP-Binding Proteins / metabolism
Multiprotein Complexes / metabolism*
Muscle, Skeletal / metabolism
Neurons / cytology
Neurons / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
RNA Interference
Sequence Alignment
Signal Transduction
TOR Serine-Threonine Kinases / metabolism*

Substances

Amino Acids
Insulin
MicroRNAs
Multiprotein Complexes
RRAGD protein, human
MAP4K3 protein, human
Mechanistic Target of Rapamycin Complex 1
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
Monomeric GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding