Mol Cell 2011,
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
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.
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mTORC1 → TSC2: " Additionally, NO inhibits IKKß and reduces AMPK phosphorylation, leading to mTORC1
activation via TSC2
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