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. Epub 2015 Jun 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Autoimmunity / genetics
  • Autophagy / genetics*
  • Cell Line, Tumor
  • Cells, Cultured
  • Class Ia Phosphatidylinositol 3-Kinase / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Cryptococcus neoformans / genetics
  • Cryptococcus neoformans / metabolism
  • DEAD-box RNA Helicases / genetics*
  • DEAD-box RNA Helicases / metabolism
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Female
  • Gene Expression Regulation, Fungal
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Inflammasomes / genetics
  • Inflammasomes / metabolism
  • Mice, Inbred C57BL
  • Mutation
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Stability / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • Inflammasomes
  • RNA, Messenger
  • Saccharomyces cerevisiae Proteins
  • mRNA decapping enzymes
  • Class Ia Phosphatidylinositol 3-Kinase
  • Protein Serine-Threonine Kinases
  • target of rapamycin protein, S cerevisiae
  • DCP2 protein, S cerevisiae
  • Endoribonucleases
  • DHH1 protein, S cerevisiae
  • DEAD-box RNA Helicases