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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / metabolism
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Autophagy*
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Beclin-1
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Cell Line
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Class III Phosphatidylinositol 3-Kinases / metabolism
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Enzyme Inhibitors / pharmacology
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HEK293 Cells
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HeLa Cells
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Humans
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Huntingtin Protein
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Huntington Disease / metabolism
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Huntington Disease / pathology
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I-kappa B Kinase / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Membrane Proteins / metabolism
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Mice
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Mitogen-Activated Protein Kinase 8 / metabolism
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Multiprotein Complexes
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NG-Nitroarginine Methyl Ester / pharmacology
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Nerve Tissue Proteins / metabolism
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Nitric Oxide / biosynthesis
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein Isoforms / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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TOR Serine-Threonine Kinases
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / metabolism
Substances
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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Enzyme Inhibitors
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Htt protein, mouse
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Huntingtin Protein
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Membrane Proteins
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Multiprotein Complexes
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Nerve Tissue Proteins
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Nuclear Proteins
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Protein Isoforms
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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TSC2 protein, human
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Tsc2 protein, mouse
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Tsc2 protein, rat
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Nitric Oxide
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Nitric Oxide Synthase
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Class III Phosphatidylinositol 3-Kinases
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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I-kappa B Kinase
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Mitogen-Activated Protein Kinase 8
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NG-Nitroarginine Methyl Ester