mTOR S-nitrosylation inhibits autophagy and lysosomal proteolysis
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 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..
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Preprint| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
bioRxiv.org - (2020) vom: 14. Sept. Zur Gesamtaufnahme - year:2020 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tan, Bryce W.Q. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2020.09.11.292607 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
XBI018736122 |
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| 520 | |a 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 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. | ||
| 700 | 1 | |a Tan, Sijie |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Byorn W.L. |e verfasserin |4 aut | |
| 700 | 1 | |a Navakkode, Sheeja |e verfasserin |4 aut | |
| 700 | 1 | |a Ng, Cheng Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Mui Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Shi |e verfasserin |4 aut | |
| 700 | 1 | |a Chai, Chou |e verfasserin |4 aut | |
| 700 | 1 | |a Chew, Katherine C.M. |e verfasserin |4 aut | |
| 700 | 1 | |a Tai, Yee Kit |e verfasserin |4 aut | |
| 700 | 1 | |a Sajikumar, Sreedharan |e verfasserin |4 aut | |
| 700 | 1 | |a Lam, Yulin |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Han-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Kah-Leong |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Esther |e verfasserin |4 aut | |
| 700 | 1 | |a Soong, Tuck Wah |e verfasserin |4 aut | |
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