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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Available from: Risheng Xu, Sep 30, 2015
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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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    • "It is proposed that H 2 S could modify cysteine residues on proteins through S-sulfhydration and subsequently alter the functions of target proteins. For example , in animals, a total of 39 proteins modified by Ssulfhydration were first discovered through biotin switch method and all of them have critical functions, including ion channel flux (Munaron et al. 2013), suppression of apoptosis and cellular senescence (Sen et al. 2012; Yang et al. 2013), regulation of ER stress response (Krishnan et al. 2011) and enhancement of various enzymatic activities (Vandiver et al. 2013). However, the study of protein S-sulfhydration in plants has just begun. "
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    ABSTRACT: Background and Aims In plants, hydrogen sulfide (H2S) acting as a gasotransmitter plays an important role in alleviating toxicity of Cd stresses. It is well known that Calcium-Dependent Protein Kinases (CDPKs) can regulate cell recognition and signal transduction through reversible protein phosphorylation, but how CDPKs regulate H2S signal remains unclear. Methods We studied on it through the genetic and pharmacological method together with spectrophotometry and LC-MS/MS. Results Our results indicated that Arabidopsis pretreated with H2S exhibited enhanced tolerance to Cd. After treatment by trifluoroperazine (TFP), the toxicity of Cd was aggravated. Meanwhile, the activity of L-cysteine desulfhydrase (LCD) was reduced and the content of endogenous H2S decreased. In vitro experiments demonstrated that CDPK3 could raise LCD activity. Interestingly, expressions of Cd associated genes could not properly respond to Cd stress in cdpk3 whereas increased when this mutant was pretreated with H2S. S-sulfhydration results revealed that the content of glutathione persulfide (GSSH) was significantly lower in lcd and cdpk3 mutants. The results indicating that the decrease in GSSH content was mainly due to the reduction in H2S, which further caused the sensitive to Cd. Conclusions CDPKs can enhance the tolerance to Cd in Arabidopsis through the way of intensifying H2S signal.
    Plant and Soil 08/2015; DOI:10.1007/s11104-015-2643-x · 2.95 Impact Factor
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    • "However , these proteomes were acquired one modification at a time and in different organs and cells, not permitting critical investigations into the interface, complementation, and organization of these modifications at the proteome level. This is important, considering that isolated instances of documented complementation and coordination between multiple modifications can regulate essential biological functions such as neurotransmission , redox-dependent signaling, and metabolism (Sen et al., 2012). Therefore, acquisition of endogenous site-specific proteomes of all four cysteine modifications simultaneously from the same organ under physiological conditions will enable comprehensive and global evaluation of complementation and coordination while providing a rich resource for appreciating cysteine modifications in biology. "
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    ABSTRACT: S-Acylation, S-glutathionylation, S-nitrosylation, and S-sulfenylation are prominent, chemically distinct modifications that regulate protein function, redox sensing, and trafficking. Although the biological significance of these modifications is increasingly appreciated, their integration in the proteome remains unknown. Novel mass spectrometry-based technologies identified 2,596 predominately unique sites in 1,319 mouse liver proteins under physiological conditions. Structural analysis localized the modifications in unique, evolutionary conserved protein segments, outside commonly annotated functional regions. Contrary to expectations, propensity for modification did not correlate with biophysical properties that regulate cysteine reactivity. However, the in vivo chemical reactivity is fine-tuned for specificity, demonstrated by the nominal complementation between the four modifications and quantitative proteomics which showed that a reduction in S-nitrosylation is not correlated with increased S-glutathionylation. A comprehensive survey uncovered clustering of modifications within biologically related protein networks. The data provide the first evidence for the occurrence of distinct, endogenous protein networks that undergo redox signaling through specific cysteine modifications. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Chemistry & biology 07/2015; 22(7). DOI:10.1016/j.chembiol.2015.06.010 · 6.65 Impact Factor
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