A Peroxiredoxin Promotes H2O2 Signaling and Oxidative Stress Resistance by Oxidizing a Thioredoxin Family Protein

Brown, Jonathon D.; Day, Alison M.; Taylor, Sarah R.; Tomalin, Lewis; Morgan, Brian A.; Veal, Elizabeth A.

doi:10.1016/j.celrep.2013.10.036

Cited by 62 publications

(62 citation statements)

References 43 publications

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“…Redox-sensitive proteins, such as Keap1, or thioredoxin-like proteins have exposed reactive thiols that serve as molecular switches that are modified under oxidizing conditions. These modified forms can be detected by changes in mobility observed by nonreducing SDS-PAGE (48)(49)(50). Vero cells were infected with HA32 at an MOI of 3 for 9 h, treated with 5 mM H 2 O 2 for various times, and harvested in the presence of NEM buffer to prevent the spontaneous formation of disulfide bonds upon lysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Putative Herpes Simplex Virus 1 Chaperone Protein UL32 Modulates Disulfide Bond Formation during Infection

Albright

Kosinski

Szczepaniak

et al. 2015

J Virol

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During DNA encapsidation, herpes simplex virus 1 (HSV-1) procapsids are converted to DNA-containing capsids by a process involving activation of the viral protease, expulsion of the scaffold proteins, and the uptake of viral DNA. Encapsidation requires six minor capsid proteins (UL6, UL15, UL17, UL25, UL28, and UL33) and one viral protein, UL32, not found to be associated with capsids. Although functions have been assigned to each of the minor capsid proteins, the role of UL32 in encapsidation has remained a mystery. Using an HSV-1 variant containing a functional hemagglutinin-tagged UL32, we demonstrated that UL32 was synthesized with true late kinetics and that it exhibited a previously unrecognized localization pattern. At 6 to 9 h postinfection (hpi), UL32 accumulated in viral replication compartments in the nucleus of the host cell, while at 24 hpi, it was additionally found in the cytoplasm. A newly generated UL32-null mutant was used to confirm that although B capsids containing wild-type levels of capsid proteins were synthesized, these procapsids were unable to initiate the encapsidation process. Furthermore, we showed that UL32 is redox sensitive and identified two highly conserved oxidoreductase-like C-X-X-C motifs that are essential for protein function. In addition, the disulfide bond profiles of the viral proteins UL6, UL25, and VP19C and the viral protease, VP24, were altered in the absence of UL32, suggesting that UL32 may act to modulate disulfide bond formation during procapsid assembly and maturation. IMPORTANCEAlthough functions have been assigned to six of the seven required packaging proteins of HSV, the role of UL32 in encapsidation has remained a mystery. UL32 is a cysteine-rich viral protein that contains C-X-X-C motifs reminiscent of those in proteins that participate in the regulation of disulfide bond formation. We have previously demonstrated that disulfide bonds are required for the formation and stability of the viral capsids and are also important for the formation and stability of the UL6 portal ring. In this report, we demonstrate that the disulfide bond profiles of the viral proteins UL6, UL25, and VP19C and the viral protease, VP24, are altered in cells infected with a newly isolated UL32-null mutant virus, suggesting that UL32 acts as a chaperone capable of modulating disulfide bond formation. Furthermore, these results suggest that proper regulation of disulfide bonds is essential for initiating encapsidation.T he products of herpes simplex virus 1 (HSV-1) DNA replication are head-to-tail concatemers that are resolved into monomeric genomic units and packaged into a procapsid shell in the nucleus of the infected cell (reviewed in references 1 to 3). The procapsid is comprised of the major capsid protein (VP5), triplex proteins (VP19C and VP23), and a dodecameric UL6 portal ring. The precursor of the viral protease (UL26) and the scaffolding protein (UL26.5) form a scaffold around which the capsid shell assembles (3, 4). During DNA encapsidation, the viral protease (V...

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Section: Resultsmentioning

confidence: 99%

The Putative Herpes Simplex Virus 1 Chaperone Protein UL32 Modulates Disulfide Bond Formation during Infection

Albright

Kosinski

Szczepaniak

et al. 2015

J Virol

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“…Mammalian Prxs also participate in the regulation of signal transduction by controlling the cytokine-induced peroxide levels [4–6]. Humans and other mammals possess six Prx isoforms, including four typical 2-cysteine (2-Cys Prxs) (Prx1–4), an atypical 2-Cys Prx5 and a 1-Cys Prx6 [7–9].…”

Section: Introductionmentioning

confidence: 99%

Peroxiredoxin 1 (Prx1) is a dual-function enzyme by possessing Cys-independent catalase-like activity

Sun

Dong

Shao

et al. 2017

Biochemical Journal

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Peroxiredoxin (Prx) was previously known as a Cys-dependent thioredoxin. However, we unexpectedly observed that Prx1 from the green spotted puffer fish Tetraodon nigroviridis (TnPrx1) was able to reduce H2O2 in a manner independent of Cys peroxidation and reductants. This study aimed to validate a novel function for Prx1, delineate the biochemical features and explore its antioxidant role in cells. We have confirmed that Prx1 from the puffer fish and humans truly possesses a catalase (CAT)-like activity that is independent of Cys residues and reductants, but dependent on iron. We have identified that the GVL motif was essential to the CAT-like activity of Prx1, but not to the Cys-dependent thioredoxin peroxidase (POX) activity, and generated mutants lacking POX and/or CAT-like activities for individual functional validation. We discovered that the TnPrx1 POX and CAT-like activities possessed different kinetic features in the reduction of H2O2. The overexpression of wild-type TnPrx1 and mutants differentially regulated the intracellular levels of reactive oxygen species (ROS) and the phosphorylation of p38 in HEK-293T cells treated with H2O2. Prx1 is a dual-function enzyme by acting as POX and CAT with varied affinities towards ROS. This study extends our knowledge on Prx1 and provides new opportunities to further study the biological roles of this family of antioxidants.

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“…At low H 2 O 2 concentration, thioredoxin peroxidase Tpx1 is oxidized to its disulfide form, which leads to oxidization of the proteasome-associated thioredoxin-like protein Txl1, as well as Pap1 (7,8). Oxidized Pap1 relocates from the cytoplasm to the nucleus as it bypasses nuclear export by Crm1 (Exportin1), forms a heterodimer with transcription factor Prr1, and turns on the expression of target genes (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…Oxidized Pap1 relocates from the cytoplasm to the nucleus as it bypasses nuclear export by Crm1 (Exportin1), forms a heterodimer with transcription factor Prr1, and turns on the expression of target genes (9,10). At a higher H 2 O 2 level, hyper-oxidized Tpx1 fails to oxidize Txl1, permitting reduced Txl1 to reduce Pap1 and turn off the early stress response (7,11). The Sty1–Atf1 pathway takes over with a phosphorelay system comprising of histidine kinase sensors Mak2 and Mak3 that passes the signal to the histidine-containing phosphorelay protein Mpr1, then to response regulator Mcs4, and finally through the MAPK cascade to the MAPK Sty1 (12).…”

Section: Introductionmentioning

confidence: 99%

A Pap1–Oxs1 signaling pathway for disulfide stress inSchizosaccharomyces pombe

He¹,

Chen²,

Song³

et al. 2016

Nucleic Acids Res

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We describe a Pap1–Oxs1 pathway for diamide-induced disulfide stress in Schizosaccharomyces pombe, where the nucleocytoplasmic HMG protein Oxs1 acts cooperatively with Pap1 to regulate transcription. Oxs1 and Pap1 form a complex when cells are exposed to diamide or Cd that causes disulfide stress. When examined for promoters up-regulated by diamide, effective Pap1 binding to these targets requires Oxs1, and vice versa. With some genes, each protein alone enhances transcription, but the presence of both exerts an additive positive effect. In other genes, although transcription is induced by diamide, Oxs1 or Pap1 plays a negative role with full de-repression requiring loss of both proteins. In a third class of genes, Oxs1 positively regulates expression, but in its absence, Pap1 plays a negative role. The Oxs1–Pap1 regulatory interaction appears evolutionarily conserved, as heterologous (human, mouse and Arabidopsis) Oxs1 and Pap1-homologues can bind interchangeably with each other in vitro, and at least in the fission yeast, heterologous Oxs1 and Pap1-homologues can substitute for S. pombe Oxs1 and Pap1 to enhance stress tolerance.

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A Peroxiredoxin Promotes H2O2 Signaling and Oxidative Stress Resistance by Oxidizing a Thioredoxin Family Protein

Cited by 62 publications

References 43 publications

The Putative Herpes Simplex Virus 1 Chaperone Protein UL32 Modulates Disulfide Bond Formation during Infection

The Putative Herpes Simplex Virus 1 Chaperone Protein UL32 Modulates Disulfide Bond Formation during Infection

Peroxiredoxin 1 (Prx1) is a dual-function enzyme by possessing Cys-independent catalase-like activity

A Pap1–Oxs1 signaling pathway for disulfide stress inSchizosaccharomyces pombe

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