Thioredoxin-mediated Denitrosylation Regulates Cytokine-induced Nuclear Factor κB (NF-κB) Activation

Kelleher, Zachary T.; Sha, Yi‐Gao; Foster, Matthew W.; Foster, W. Michael; Forrester, Michael T.; Marshall, Hiram W.

doi:10.1074/jbc.m113.503938

Cited by 69 publications

(53 citation statements)

References 27 publications

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“…Our findings suggest that the Trx system may also contribute to maintaining iNOS in a denitrosylated, active state. Our data also support the idea that Trx promotes iNOS activity by denitrosylating and activating signaling proteins involved in the transcriptional activation of iNOS, such as MEK1 and NF-B (28,54). It should be noted that Trx can also promote iNOS activity via the recently reported GAPDH-heme insertion mechanism (14).…”

Section: Discussionsupporting

confidence: 74%

A Substrate Trapping Approach Identifies Proteins Regulated by Reversible S-nitrosylation

Ben-Lulu

Ziv

Admon

et al. 2014

Molecular & Cellular Proteomics

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Protein S-nitrosylation, the nitric oxide-mediated posttranslational modification of cysteine residues, has emerged as an important regulatory mechanism in diverse cellular processes. Yet, knowledge about the Snitrosoproteome in different cell types and cellular contexts is still limited and many questions remain regarding the precise roles of protein S-nitrosylation and denitrosylation. Here we present a novel strategy to identify reversibly nitrosylated proteins. Our approach is based on nitrosothiol capture and enrichment using a thioredoxin trap mutant, followed by protein identification by mass spectrometry. Employing this approach, we identified more than 400 putative nitroso-proteins in S-nitrosocysteinetreated human monocytes and about 200 nitrosylation substrates in endotoxin and cytokine-stimulated mouse macrophages. The large majority of these represent novel nitrosylation targets and they include many proteins with key functions in cellular homeostasis and signaling. Biochemical and functional experiments in vitro and in cells validated the proteomic results and further suggested a role for thioredoxin in the denitrosylation and activation of inducible nitric oxide synthase and the protein kinase MEK1. Our findings contribute to a better understanding of the macrophage S-nitrosoproteome and the role of thioredoxin-mediated denitrosylation in nitric oxide signaling. The approach described here may prove generally useful for the identification and exploration of nitrosoproteomes under various physiological and pathophysiological conditions. Molecular & Cellular

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Section: Discussionsupporting

confidence: 74%

A Substrate Trapping Approach Identifies Proteins Regulated by Reversible S-nitrosylation

Ben-Lulu

Ziv

Admon

et al. 2014

Molecular & Cellular Proteomics

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“…Denitrosylation of NPR1 is reminiscent of the mammalian immune-induced NF-kB transcription factor, whose activity is also suppressed by site-specific S-nitrosylation in respiratory epithelium. Upon cytokine stimulation, NF-kB is denitrosylated by TRX1, thereby promoting its transcriptional activity (Kelleher et al, 2014). Despite promoting nuclear translocation of NPR1, denitrosylation activity of TRXh5 was insufficient to restore immuneinduced gene expression in gsnor1 mutants ( Figures 5B-5D).…”

Section: Molecular Cellmentioning

confidence: 99%

“…Accordingly, plant cells exhibited strong denitrosylation activity that was dependent on the activity of NTR ( Figures 1C-1G). In this respect, plant TRX-h enzymes behave similar to the mammalian TRX system, which has been described as a potent protein-SNO reductase involved in a variety of processes, including apoptosis and inflammatory signaling (Benhar et al, 2008;Kelleher et al, 2014). Mammalian TRX1 in the disulphide form, however, was shown to be S-nitrosylated at a cysteine residue away from the active site, allowing it to also function as a NO donor by trans-nitrosylating target proteins (Mitchell and Marletta, 2005;Sengupta and Holmgren, 2013).…”

Section: Molecular Cellmentioning

confidence: 99%

Selective Protein Denitrosylation Activity of Thioredoxin-h5 Modulates Plant Immunity

et al. 2014

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In eukaryotes, bursts of reactive oxygen and nitrogen species mediate cellular responses to the environment by modifying cysteines of signaling proteins. Cysteine reactivity toward nitric oxide (NO) leads to formation of S-nitrosothiols (SNOs) that play important roles in pathogenesis and immunity. However, it remains poorly understood how SNOs are employed as specific, reversible signaling cues. Here we show that in plant immunity the oxidoreductase Thioredoxin-h5 (TRXh5) reverses SNO modifications by acting as a selective protein-SNO reductase. While TRXh5 failed to restore immunity in gsnor1 mutants that display excessive accumulation of the NO donor S-nitrosoglutathione, it rescued immunity in nox1 mutants that exhibit elevated levels of free NO. Rescue by TRXh5 was conferred through selective denitrosylation of excessive protein-SNO, which reinstated signaling by the immune hormone salicylic acid. Our data indicate that TRXh5 discriminates between protein-SNO substrates to provide previously unrecognized specificity and reversibility to protein-SNO signaling in plant immunity.

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“…As a result of this dissociation, TXNIP would be free to bind to, induce IL‐1β secretion (Park et al, ), and activate inflammation (Thompson et al, ). In addition, promotion of Trx activity in the lung increased NF‐κB activation, and airway inflammation, which supported the mechanism of pathophysiological role in lung injury (Kelleher et al, ). Meanwhile, these pro‐inflammatory factors enhanced oxidative stress.…”

Section: Discussionmentioning

confidence: 53%

Curcumin alleviated the toxic reaction of Rhizoma Paridis saponins in a 45-day subchronic toxicological assessment of rats

Man

Liu

et al. 2015

Environ. Toxicol.

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Rhizoma Paridis saponins (RPS), as steroid saponins, are the main components in Paris polyphylla. Curcumin (diferuloylmethane) is the most important component in the spice turmeric. In our previous research, RPS exhibited side effects such as nausea, vomiting, diarrhea, and so forth. Combination with curcumin not only alleviated the toxicity and gastric stimulus induced by RPS, but also improved the quality life of mice bearing tumor cells and enhanced their anticancer effect. This study evaluated subchronic toxicity of 45 dietary of RPS and curcumin on histopathology, biochemistry, and antioxidant index. As a result, RPS-treatment caused a slight liver injury (the elevation of serum AST, alkaline phosphatase (AKP), alanine transaminase (ALT), and gamma glutamyl transpeptidase (γ-GT), histopathological changes in liver section), oxidative stress (the enhancement of reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OHdG), separation of thioredoxin (Trx) and thioredoxin-interacting protein (TXNIP), but enhancement of heme oxygenase-1 (HO-1), glutathione S-transferase (GST), and nuclear factor-regulated factor 2 (Nrf2)), and inflammation (up-regulation of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and nuclear factor kappaB (NF-κB)). However, these changes were alleviated through co-treatment with curcumin. In conclusion, our work provided useful data for further research and new drug exploration of RPS and curcumin. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1935-1943, 2016.

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Thioredoxin-mediated Denitrosylation Regulates Cytokine-induced Nuclear Factor κB (NF-κB) Activation

Cited by 69 publications

References 27 publications

A Substrate Trapping Approach Identifies Proteins Regulated by Reversible S-nitrosylation

A Substrate Trapping Approach Identifies Proteins Regulated by Reversible S-nitrosylation

Selective Protein Denitrosylation Activity of Thioredoxin-h5 Modulates Plant Immunity

Curcumin alleviated the toxic reaction of Rhizoma Paridis saponins in a 45-day subchronic toxicological assessment of rats

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