Cargando…

Complex Inhibitory Effects of Nitric Oxide on Autophagy

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149661/
https://www.ncbi.nlm.nih.gov/pubmed/21726807
http://dx.doi.org/10.1016/j.molcel.2011.04.029
Descripción
Sumario: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.