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

• Published in: Nature cell biology Vol. 17; no. 7; pp. 930 - 942
• Main Authors: Hu, Guowu, McQuiston, Travis, Bernard, Amélie, Park, Yoon-Dong, Qiu, Jin, Vural, Ali, Zhang, Nannan, Waterman, Scott R., Blewett, Nathan H., Myers, Timothy G., Maraia, Richard J., Kehrl, John H., Uzel, Gulbu, Klionsky, Daniel J., Williamson, Peter R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2015; Nature Publishing Group
• Subjects: 13/31; 14/32; 38/32; 45/22; 45/23; 45/77; 45/88; 49/61; 631/80/39; 96/34; 96/63; Animals; Autoimmunity - genetics; Autophagy (Cytology); Autophagy - genetics; Cancer Research; Cell Biology; Cell Line, Tumor; Cells, Cultured; Cellular control mechanisms; 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; Developmental Biology; Endoribonucleases - genetics; Endoribonucleases - metabolism; Female; Gene Expression Regulation, Fungal; Genetic aspects; HeLa Cells; Humans; Immunoblotting; Inflammasomes - genetics; Inflammasomes - metabolism; Life Sciences; Mammals; Messenger RNA; Mice, Inbred C57BL; Mutation; Phosphorylation; Properties; Protein-Serine-Threonine Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Stability - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Stem Cells; Yeasts
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3189

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. Williamson and colleagues demonstrate that mRNA-decapping enzyme Dcp2 is phosphorylated by mTORC1, leading to degradation of Atg mRNA and suppression of autophagy, influencing immunity and inflammation.