Complex Inhibitory Effects of Nitric Oxide on Autophagy

• Published in: Molecular cell Vol. 43; no. 1; pp. 19 - 32
• Main Authors: Sarkar, Sovan, Korolchuk, Viktor I., Renna, Maurizio, Imarisio, Sara, Fleming, Angeleen, Williams, Andrea, Garcia-Arencibia, Moises, Rose, Claudia, Luo, Shouqing, Underwood, Benjamin R., Kroemer, Guido, O'Kane, Cahir J., Rubinsztein, David C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.07.2011; Cell Press
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; Autophagy; Beclin-1; Cell Line; Class III Phosphatidylinositol 3-Kinases - metabolism; endothelial nitric oxide synthase; Enzyme Inhibitors - pharmacology; HEK293 Cells; HeLa Cells; Humans; Huntingtin Protein; Huntington Disease - metabolism; Huntington Disease - pathology; I-kappa B Kinase - metabolism; inducible nitric oxide synthase; Mechanistic Target of Rapamycin Complex 1; Membrane Proteins - metabolism; Mice; Mitogen-Activated Protein Kinase 8 - metabolism; Multiprotein Complexes; Nerve Tissue Proteins - metabolism; neurodegenerative diseases; neuronal nitric oxide synthase; NG-Nitroarginine Methyl Ester - pharmacology; nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nuclear Proteins - metabolism; Phosphorylation; Protein Isoforms - metabolism; proteins; Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.04.029

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. [Display omitted] ► NO inhibits autophagy by independently inhibiting JNK1 and IKKβ ► NO inhibits autophagic flux via mTOR and mTOR-independent routes ► NOS overexpression impairs autophagosome synthesis via JNK1–Bcl-2 pathway ► NOS inhibition induces autophagy and protects against neurodegeneration