Hydrogen Sulfide-Linked Sulfhydration of NF-κB Mediates Its Antiapoptotic Actions

The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Molecular cell (Impact Factor: 14.02). 01/2012; 45(1):13-24. DOI: 10.1016/j.molcel.2011.10.021
Source: PubMed


Nuclear factor κB (NF-κB) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-κB are mediated by hydrogen sulfide (H(2)S) synthesized by cystathionine gamma-lyase (CSE). TNF-α treatment triples H(2)S generation by stimulating binding of SP1 to the CSE promoter. H(2)S generated by CSE stimulates DNA binding and gene activation of NF-κB, processes that are abolished in CSE-deleted mice. As CSE deletion leads to decreased glutathione levels, resultant oxidative stress may contribute to alterations in CSE mutant mice. H(2)S acts by sulfhydrating the p65 subunit of NF-κB at cysteine-38, which promotes its binding to the coactivator ribosomal protein S3 (RPS3). Sulfhydration of p65 predominates early after TNF-α treatment, then declines and is succeeded by a reciprocal enhancement of p65 nitrosylation. In CSE mutant mice, antiapoptotic influences of NF-κB are markedly diminished. Thus, sulfhydration of NF-κB appears to be a physiologic determinant of its antiapoptotic transcriptional activity.

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    • " S ) - mediated signaling pathways involved in many physiological and pathophysiological processes ( Abe & Kimura , 1996 ; Eberhardt et al . , 2014 ; Elrod et al . , 2007 ; Greiner et al . , 2013 ; Kabil & Banerjee , 2010 ; Krishnan , Fu , Pappin , & Tonks , 2011 ; Li , Rose , & Moore , 2011 ; Mustafa et al . , 2009 , 2011 ; Paul & Snyder , 2012 ; Sen et al . , 2012 ; Szabo , 2007 ; Vandiver et al . , 2013 ; Yang et al . , 2008 , 2013 ; Zhao , Zhang , Lu , & Wang , 2001 ) ."
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    ABSTRACT: Protein S-sulfhydration (i.e., converting protein cysteines -SH to persulfides -SSH) is a redox-based posttranslational modification. This reaction plays an important role in signaling pathways mediated by hydrogen sulfide or other reactive sulfane sulfur species. Recently, our laboratories developed a "tag-switch" method which can be used to selectively label and detect protein S-sulfhydrated residues. In this chapter, we provide a comprehensive summary of this method, including the design of the method, preparation of the reagents, validation on small-molecule substrates, as well as applications in protein labeling. Experimental protocols for the use of the method are described in details. © 2015 Elsevier Inc. All rights reserved.
    Methods in enzymology 12/2015; 555:39-56. DOI:10.1016/bs.mie.2014.11.033 · 2.09 Impact Factor
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    • "The essential role of RPS3 in directing NF-jB to a subset of genes makes it a potential target for selective NF-jB inhibition in cancer cells. Moreover, RPS3 was recently revealed as a physiologic determinant of NF-jB-mediated transcription of antiapoptotic genes in macrophages, including Birc3 (encoding cellular inhibitor of apoptosis protein-2, cIAP2), Bcl2l1 (encoding B-cell lymphoma-extra large, Bcl-XL), and Xiap (encoding X-linked inhibitor of apoptosis protein, XIAP) [26]. We recently showed that N-terminal fragments of p65, generated by ectopic expression or pathogen protease cleavage, selectively retard RPS3 nuclear translocation and RPS3-conferred NF-jB gene transcription, without affecting p65 [22] [27]. "
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    FEBS letters 11/2015; DOI:10.1016/j.febslet.2015.10.019 · 3.17 Impact Factor
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    • "The number of reports on the biological activity of H 2 S have increased exponentially in the past fifteen years owing to several factors including the availability of facile assays like methylene blue [4] [5] for detection of H 2 S in tissues; seminal papers demonstrating that H 2 S affected important processes like the regulation of ion channels [6] [7] [8]; animal knockouts of CSE can lead to large physiological changes i.e. the elevation of blood pressure [9]; the introduction of methods for detection of proteins modified by Ssulfuration [1] and the direct or indirect demonstration that the sulfuration of proteins like GAPDH [1], protein tyrosine phospha- tase-1B (PTB1B) [10], NF-κB [11], Cu/Zn superoxide dismutase [12] greatly affect their structure and function. Despite the many reports that H 2 S is involved in almost all physiological and pathophysiological processes, the field is fraught with controversy mainly resulting from difficulties in the accurate measurement of H 2 S in biological tissues. "
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