PT  - JOURNAL ARTICLE
AU  - Bryce W.Q. Tan
AU  - Sijie Tan
AU  - Byorn W.L. Tan
AU  - Sheeja Navakkode
AU  - Cheng Yang Ng
AU  - Steven Yuan
AU  - Mui Cheng Liang
AU  - Chao Liu
AU  - Shi Yin
AU  - Chou Chai
AU  - Katherine C.M. Chew
AU  - Yee Kit Tai
AU  - Sreedharan Sajikumar
AU  - Yulin Lam
AU  - Ping Liao
AU  - Han-Ming Shen
AU  - Kah-Leong Lim
AU  - Esther Wong
AU  - Tuck Wah Soong
TI  - mTOR S-nitrosylation inhibits autophagy and lysosomal proteolysis
AID  - 10.1101/2020.09.11.292607
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.11.292607
4099  - http://biorxiv.org/content/early/2020/09/11/2020.09.11.292607.short
4100  - http://biorxiv.org/content/early/2020/09/11/2020.09.11.292607.full
AB  - Mammalian Target of Rapamycin (mTOR) is a master regulator of autophagy and lysosomes, and its downstream kinase-dependent pathways have been extensively characterized. Here, we report an unexpected kinase-independent regulation of autophagy and lysosomes by S-nitrosylation at Cys423 position of mTOR that resulted in suppression of VPS34 and PIKfyve-dependent phosphoinositide synthesis. Physiologically, S-nitrosylation of mTOR reduced basal lysosomal proteolysis via nitric oxide synthase (NOS)-mediated synthesis of NO from lysosomal arginine precursor, a marker of cellular nutrition status. Significantly, we found increased lysosomal NOS-mTOR complexes in APP-PS1 Alzheimer’s disease (AD) murine model, and increased mTOR S-nitrosylation in AD patient-derived fibroblasts. Lastly, we demonstrated that pharmacological inhibition of NOS or overexpression of mTORCys423Ala mutant reversed lysosomal and autophagic dysfunction in AD patient-derived fibroblasts, suggesting novel therapeutic strategies for autophagosome-lysosomal activation.Competing Interest StatementThe authors have declared no competing interest.