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Complex inhibitory effects of nitric oxide on autophagy.

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Sarkar, Sovan 
Korolchuk, Viktor I 
Renna, Maurizio 
Imarisio, Sara 


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.



Animals, Apoptosis Regulatory Proteins, Autophagy, Beclin-1, Cell Line, Class III Phosphatidylinositol 3-Kinases, Enzyme Inhibitors, HEK293 Cells, HeLa Cells, Humans, Huntingtin Protein, Huntington Disease, I-kappa B Kinase, Mechanistic Target of Rapamycin Complex 1, 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, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins

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Mol Cell

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Elsevier BV
Medical Research Council (G0600194)
Medical Research Council (G0901339)