A Pap1–Oxs1 signaling pathway for disulfide stress in<i>Schizosaccharomyces pombe</i>

He, Yumei; Chen, Yan; Song, Wen; Zhu, Li; Dong, Zhicheng; Ow, David W.

doi:10.1093/nar/gkw818

Cited by 23 publications

(41 citation statements)

References 32 publications

(40 reference statements)

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“…To test whether any of these seven amino acid substitutions introduced into the full-length Oxs1 protein would affect its subcellular localization, each variant was fused to the C terminus of GFP. As described previously (He et al 2017), GFP-Oxs1 fluorescence can be observed in the nucleus upon treatment with diamide but not in the absence of stress ( Figure 4A). For the substitution mutants in the absence of diamide, only GFP-Oxs1 A110V , GFP-Oxs1 L113F , or GFP-Oxs1 S115G , like the GFP-Oxs1 control, retained the ability to be excluded from the nucleus (Figure 4Ba-c).…”

Section: Nuclear Exclusion Capability Associated With Diamide Tolerancesupporting

confidence: 82%

“…In vitro GST pull-down assays were performed as in He et al (2017). His-Pap1 was incubated with GST beads bound to GST or GST fused to GFP as control, GST fused to Oxs1, GST fused to Oxs1 variants with mutations in the NES, or to GST fused with an Oxs1-truncated peptide.…”

Section: In Vitro Gst Pull-down Assaymentioning

confidence: 99%

“…Pap1 and Oxs1 form a complex in vivo upon diamide or Cd treatment, which then regulates certain diamide-response genes. This regulation includes coactivation of some genes, corepression of other genes, and in a third class of genes, Oxs1 keeps Pap1 from repressing transcription (He et al 2017). To ask whether the NES peptide functions similarly to that of the full-length Oxs1, we tested the effect of pap1 + on o1NES conjugate-enhanced diamide tolerance.…”

Section: Nuclear Exclusion Capability Associated With Diamide Tolerancementioning

confidence: 99%

“…Diamide is a thiol-reactive electrophile that reacts directly and rapidly with glutathione or protein thiols, leading to the formation of disulfides or S-thiolated proteins (Hochgräfe et al 2007). We recently described a Pap1-Oxs1 pathway specific for the diamide-induced disulfide stress response in S. pombe (He et al 2017). Oxs1 is a 207 aa highmobility-group protein required for tolerance to diamide or cadmium.…”

mentioning

confidence: 99%

“…Like Pap1, Oxs1 is a conserved nucleocytoplasmic shuttling protein that enters the nucleus during stress, but is exported by exportin Crm1 in the absence of stress. Also like Pap1, Oxs1 appears to be part of an evolutionarily conserved stressresponse pathway, as functional conservation has been implicated through the ability of heterologous Oxs1 homologs to enhance diamide stress tolerance in S. pombe, as well as the ability of S. pombe, human, and Arabidopsis homologs to interchangeably bind Pap1 or Pap1 homologs human cJun and Arabidopsis bZIP10 (He et al 2017).…”

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confidence: 99%

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Protection from Disulfide Stress by Inhibition of Pap1 Nuclear Export in Schizosaccharomyces pombe

et al. 2018

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Appropriate subcellular localization of regulatory factors is critical for cellular function. Pap1, a nucleocytoplasmic shuttling transcription factor of Schizosaccharomyces pombe, is redox regulated for localization and antistress function. In this study, we find that overproduction of a peptide conjugate containing the nuclear export signal of Oxs1, a conserved eukaryotic protein that, along with Pap1, regulates certain diamide responsive genes, can retain Pap1 in the nucleus before stress by competing for nuclear export. The nuclear retention of Pap1 upregulates several drug resistance genes to prime the cells for higher tolerance to disulfide stress. Overproduction of Oxs1 also upregulates these same genes, not by competing for export but by binding directly to the drug resistance gene promoters for Pap1-mediated activation. Of medical relevance is that this may suggest a gene therapy approach of using nuclear export signal conjugates to suppress the nuclear export of biomolecules.

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Section: Nuclear Exclusion Capability Associated With Diamide Tolerancesupporting

confidence: 82%

Section: In Vitro Gst Pull-down Assaymentioning

confidence: 99%

Section: Nuclear Exclusion Capability Associated With Diamide Tolerancementioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Protection from Disulfide Stress by Inhibition of Pap1 Nuclear Export in Schizosaccharomyces pombe

et al. 2018

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TFF3 mediates the NF‐κB/COX2 pathway to regulate PMN‐MDSCs activation and protect against necrotizing enterocolitis

et al. 2021

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Intestinal trefoil factor 3 (TFF3) plays an important role in repairing the intestinal mucosa. However, the detailed mechanism regarding immune regulation by TFF3 is not well defined. Here, we reported that treatment of mouse BM cells and human peripheral blood mononuclear cells from healthy volunteers with TFF3 activated polymorphnuclear myeloid-derived suppressor cells (PMN-MDSCs) in vitro. We also found that prostaglandin E2 is a major TFF3-mediated MDSC target, and that NF-κB/COX2 signaling was involved in this process. Moreover, TFF3 treatment or transfer of TFF3-derived PMN-MDSCs (TFF3-MDSCs) to experimental necrotizing enterocolitis (NEC) mice caused PMN-MDSC accumulation in the lamina propria (LP), which was associated with decreased intestinal inflammation, permeability, bacterial loading, and prolonged survival. Interestingly, no NEC severity remission was observed in Rag1 KO mice that were given TFF3-MDSCs, but coinjection with CD4 + T cells significantly relieved NEC inflammation. Overall, TFF3 mediates the NF-κB/COX2 pathway to regulate PMN-MDSC activation and attenuates NEC in a T-cell-dependent manner, which suggests a novel mechanism in preventing NEC occurrence.

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Dimerization underlies the aggregation propensity of intrinsically disordered coiled‐coil domain‐containing 124

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2021

Proteins

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Coiled‐coil domain‐containing 124 (CCDC124) is a recently discovered ribosome‐binding protein conserved in eukaryotes. CCDC124 has regulatory functions on the mediation of reversible ribosomal hibernation and translational recovery by direct attachment to large subunit ribosomal protein uL5, 25S rRNA backbone, and tRNA‐binding P/A‐site major groove. Moreover, it independently mediates cell division and cellular stress response by facilitating cytokinetic abscission and disulfide stress‐dependent transcriptional regulation, respectively. However, the structural characterization and intracellular physiological status of CCDC124 remain unknown. In this study, we employed advanced in silico protein modeling and characterization tools to generate a native‐like tertiary structure of CCDC124 and examine the disorder, low sequence complexity, and aggregation propensities, as well as high‐order dimeric/oligomeric states. Subsequently, dimerization of CCDC124 was investigated with co‐immunoprecipitation (CO‐IP) analysis, immunostaining, and a recent live‐cell protein–protein interaction method, bimolecular fluorescence complementation (BiFC). Results revealed CCDC124 as a highly disordered protein consisting of low complexity regions at the N‐terminus and an aggregation sequence (151‐IAVLSV‐156) located in the middle region. Molecular docking and post‐docking binding free energy analyses highlighted a potential involvement of V153 residue on the generation of high‐order dimeric/oligomeric structures. Co‐IP, immunostaining, and BiFC analyses were used to further confirm the dimeric state of CCDC124 predominantly localized at the cytoplasm. In conclusion, our findings revealed in silico structural characterization and in vivo subcellular physiological state of CCDC124, suggesting low‐complexity regions located at the N‐terminus of disordered CCDC124 may regulate the formation of aggregates or high‐order dimeric/oligomeric states.

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A Pap1–Oxs1 signaling pathway for disulfide stress inSchizosaccharomyces pombe

Cited by 23 publications

References 32 publications

Protection from Disulfide Stress by Inhibition of Pap1 Nuclear Export in Schizosaccharomyces pombe

Protection from Disulfide Stress by Inhibition of Pap1 Nuclear Export in Schizosaccharomyces pombe

TFF3 mediates the NF‐κB/COX2 pathway to regulate PMN‐MDSCs activation and protect against necrotizing enterocolitis

Dimerization underlies the aggregation propensity of intrinsically disordered coiled‐coil domain‐containing 124

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