Journal
MOLECULAR CELL
Volume 43, Issue 1, Pages 19-32Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2011.04.029
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Funding
- Hughes Hall Research Fellowship
- NIHR Biomedical Research Centre at Addenbrooke's Hospital and MRC
- Action Medical Research Training Fellowship
- Ligue Nationale contre le Cancer, Agence Nationale pour la Recherche, AXA Chair for Longevity Research
- Wellcome Trust
- Medical Research Council
- Sackler Trust
- National Institute for Health Research Biomedical Research Centre at Addenbrooke's Hospital
- MRC [G0600194, G0901339] Funding Source: UKRI
- Medical Research Council [G0600194, G0901339] Funding Source: researchfish
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Autophagy, a major degradation process for long-lived and aggregate-prone proteins, affects various human processes, such as development, immunity, cancer, and neurodegeneration. Several autophagy regulators have been identified in recent years. Here we show that nitric oxide (NO), a potent cellular messenger, inhibits autophagosome synthesis via a number of mechanisms. NO impairs autophagy by inhibiting the activity of S-nitrosylation substrates, JNK1 and IKK beta. Inhibition of JNK1 by NO reduces Bcl-2 phosphorylation and increases the Bcl-2-Beclin 1 interaction, thereby disrupting hVps34/Beclin 1 complex formation. Additionally, NO inhibits IKK beta and reduces AMPK phosphorylation, leading to mTORC1 activation via TSC2. Overexpression of nNOS, iNOS, or eNOS impairs autophagosome formation primarily via the JNK1-Bcl-2 pathway. Conversely, NOS inhibition enhances the clearance of autophagic substrates and reduces neurodegeneration in models of Huntington's disease. Our data suggest that nitrosative stress-mediated protein aggregation in neurodegenerative diseases may be, in part, due to autophagy inhibition.
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