mTOR S-nitrosylation inhibits autophagy and lysosomal proteolysis
Tan, B. W. Q.; Tan, S.; Tan, B. W. L.; Navakkode, S.; Ng, C. Y.; Yuan, S.; Liang, M. C.; Liu, C.; Yin, S.; Chai, C.; Chew, K. C. M.; Tai, Y. K.; Sreedharan, S.; Lam, Y.; Liao, P.; Shen, H.-M.; Lim, K. L.; Wong, E.; Soong, T. W.
Show abstract
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 Alzheimers 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.
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