Complex inhibitory effects of nitric oxide on autophagy

Mol Cell. 2011 Jul 8;43(1):19-32. doi: 10.1016/j.molcel.2011.04.029.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Huntington Disease / 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
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / 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

Substances

  • 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
  • TOR Serine-Threonine Kinases
  • Class III Phosphatidylinositol 3-Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • I-kappa B Kinase
  • Mitogen-Activated Protein Kinase 8
  • NG-Nitroarginine Methyl Ester