2. Academic Validation
  3. A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy

A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy

  • Nat Cell Biol. 2015 Jul;17(7):930-942. doi: 10.1038/ncb3189.
Guowu Hu # 1,  Travis McQuiston # 1,  Amélie Bernard # 2,  Yoon-Dong Park 1,  Jin Qiu 1,  Ali Vural 3,  Nannan Zhang 1,  Scott R Waterman 1,  Nathan H Blewett 4,  Timothy G Myers 5,  Richard J Maraia 4,  John H Kehrl 3,  Gulbu Uzel 1,  Daniel J Klionsky 2,  Peter R Williamson 1
Affiliations

Affiliations

  • 1 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
  • 2 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 48109.
  • 3 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
  • 4 Intramural Research Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
  • 5 Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA, 20892.
  • # Contributed equally.
PMID: 26098573 DOI: 10.1038/ncb3189
Abstract

Autophagy is an essential eukaryotic pathway requiring tight regulation to maintain homeostasis and preclude disease. Using yeast and mammalian cells, we report a conserved mechanism of Autophagy regulation by RNA helicase RCK family members in association with the decapping Enzyme Dcp2. Under nutrient-replete conditions, Dcp2 undergoes TOR-dependent phosphorylation and associates with RCK members to form a complex with autophagy-related (ATG) mRNA transcripts, leading to decapping, degradation and Autophagy suppression. Simultaneous with the induction of ATG mRNA synthesis, starvation reverses the process, facilitating ATG mRNA accumulation and Autophagy induction. This conserved post-transcriptional mechanism modulates Fungal virulence and the mammalian inflammasome, the latter providing mechanistic insight into autoimmunity reported in a patient with a PIK3CD/p110δ gain-of-function mutation. We propose a dynamic model wherein RCK family members, in conjunction with Dcp2, function in controlling ATG mRNA stability to govern Autophagy, which in turn modulates vital cellular processes affecting inflammation and microbial pathogenesis.

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