NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1

The Journal of Experimental Medicine
Mirza Saqib BaigMarcelo G Bonini

Abstract

The NF-κB pathway is central to the regulation of inflammation. Here, we demonstrate that the low-output nitric oxide (NO) synthase 1 (NOS1 or nNOS) plays a critical role in the inflammatory response by promoting the activity of NF-κB. Specifically, NOS1-derived NO production in macrophages leads to proteolysis of suppressor of cytokine signaling 1 (SOCS1), alleviating its repression of NF-κB transcriptional activity. As a result, NOS1(-/-) mice demonstrate reduced cytokine production, lung injury, and mortality when subjected to two different models of sepsis. Isolated NOS1(-/-) macrophages demonstrate similar defects in proinflammatory transcription on challenge with Gram-negative bacterial LPS. Consistently, we found that activated NOS1(-/-) macrophages contain increased SOCS1 protein and decreased levels of p65 protein compared with wild-type cells. NOS1-dependent S-nitrosation of SOCS1 impairs its binding to p65 and targets SOCS1 for proteolysis. Treatment of NOS1(-/-) cells with exogenous NO rescues both SOCS1 degradation and stabilization of p65 protein. Point mutation analysis demonstrated that both Cys147 and Cys179 on SOCS1 are required for its NO-dependent degradation. These findings demonstrate a fundamental role fo...Continue Reading

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Citations

Oct 27, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Lijun WuWenrong Xu
Jul 7, 2018·Critical Care Medicine·Francisco Vasques-NóvoaRoberto Roncon-Albuquerque
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Methods Mentioned

BETA
targeted mutations
nuclear translocation
ELISA
transgenic
ubiquitination
Co-immunoprecipitation
genotyping
Assay
PCR

Software Mentioned

CHARMM
Protein Model Port
Sequence Manipulation Suite
ImageJ
Prism
AutoDock
GraphPad
Mcule
Excel
Tasser

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