Abstract
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 IKKβ. 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 IKKβ 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.
Original language | English |
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Pages (from-to) | 19-32 |
Number of pages | 14 |
Journal | Molecular Cell |
Volume | 43 |
Issue number | 1 |
DOIs | |
Publication status | Published - 8 Jul 2011 |
Keywords
- Animals
- Apoptosis Regulatory Proteins
- Autophagy
- Cell Line
- Class III Phosphatidylinositol 3-Kinases
- Enzyme Inhibitors
- HEK293 Cells
- HeLa Cells
- Humans
- Huntington Disease
- I-kappa B Kinase
- Membrane Proteins
- Mice
- Mitogen-Activated Protein Kinase 8
- Multiprotein Complexes
- NG-Nitroarginine Methyl Ester
- Nerve Tissue Proteins
- Nitric Oxide
- Nitric Oxide Synthase
- Nuclear Proteins
- Phosphorylation
- Protein Isoforms
- Proteins
- Proto-Oncogene Proteins c-bcl-2
- Rats
- TOR Serine-Threonine Kinases
- Tumor Suppressor Proteins