Complex inhibitory effects of nitric oxide on autophagy.

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.

• Authors: Sovan Sarkar, Viktor I Korolchuk, Maurizio Renna, Sara Imarisio, Angeleen Fleming, Andrea Williams, Moises Garcia-Arencibia, Claudia Rose, Shouqing Luo, Benjamin R Underwood, Guido Kroemer, Cahir J O'Kane, David C Rubinsztein
• Journal: Molecular cell (Mol Cell) Vol. 43 Issue 1 Pg. 19-32 (Jul 08 2011) ISSN: 1097-4164 [Electronic] United States
• PMID: 21726807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Enzyme Inhibitors
• Htt protein, mouse
• Huntingtin Protein
• Membrane Proteins
• Multiprotein Complexes
• Nerve Tissue Proteins
• Nuclear Proteins
• Protein Isoforms
• Proteins
• Proto-Oncogene Proteins c-bcl-2
• TSC2 protein, human
• Tsc2 protein, mouse
• Tsc2 protein, rat
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• Nitric Oxide
• Nitric Oxide Synthase
• Class III Phosphatidylinositol 3-Kinases
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• I-kappa B Kinase
• Mitogen-Activated Protein Kinase 8
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy
• Beclin-1
• Cell Line
• Class III Phosphatidylinositol 3-Kinases (metabolism)
• Enzyme Inhibitors (pharmacology)
• HEK293 Cells
• HeLa Cells
• Humans
• Huntingtin Protein
• Huntington Disease (metabolism, pathology)
• I-kappa B Kinase (metabolism)
• Mechanistic Target of Rapamycin Complex 1
• Membrane Proteins (metabolism)
• Mice
• Mitogen-Activated Protein Kinase 8 (metabolism)
• Multiprotein Complexes
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nerve Tissue Proteins (metabolism)
• Nitric Oxide (biosynthesis, metabolism)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Nuclear Proteins (metabolism)
• Phosphorylation
• Protein Isoforms (metabolism)
• Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rats
• TOR Serine-Threonine Kinases
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (metabolism)