Hepatic transcriptome analysis of WT and PRDX1Cys52Ser mutant mice on CDAHFD
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE271914 | GEO | 2024/12/05
REPOSITORIES: GEO
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Project description:Objective: Peroxiredoxin 1 (PRDX1) is a peroxidase and guards against oxidative stress by scavenging intracellular peroxides, whereas it also has been shown to stimulate inflammatory response by functioning as a chaperone protein. The potential in vivo link between PRDX1’s peroxidase activity and its pro-inflammatory activity remains elusive. Methods: We generated peroxidase-dead PRDX1 variant mice by mutating its peroxidatic cysteine at 52 (Cys52) to serine, here referred to as PRDX1Cys52Ser. Trx-TrxR-NADPH coupled activity assay was applied to evaluate the peroxidase activity of global PRDX in PRDX1Cys52Ser variant mice. PRDX1Cys52Ser mice and their wild-type littermates were subjected to western diet or methionine and choline deficient diet feeding. NASH phenotypes were assessed through different analyses including physiological measurements, immunohistochemical staining, and quantitative PCR (qPCR). RNA sequencing, qPCR and western blotting were used to reveal and validate any changes in the signaling pathways responsible for the altered NASH phenotypes observed between WT and PRDX1Cys52Ser variant mice. Results: PRDX1Cys52Ser variant mice showed impaired global PRDX peroxidase activity and reduced susceptibility to diet-induced NASH and liver fibrosis. Mechanistically, PRDX1 Cys52Ser variant suppressed NF-κB signaling and STAT1 signaling pathways that are known to promote inflammation and NASH. Conclusion: The peroxidatic Cys52 of PRDX1 is required for its pro-inflammatory activity in vivo. This study further suggests that PRDX1 plays dual but opposing roles in NASH
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Project description:The etiology of non-alcoholic steatohepatitis (NASH) has been complicated. An increasing body of literature has indicated that hepatic oxidative stress exerts a causal role in driving NASH. Nevertheless, how the anti-oxidant defense system guards against oxidative stress and NASH remains unclear. In this study, we sought to investigate how the peroxidase peroxiredoxin 1 protects against NASH. To this end, we fed WT and hepatic PRDX1 knockout (Alb-Cre;Prdx1fl/fl) a methionine and choline deficient diet (MCD) for 5 weeks and collected liver samples for RNA sequencing analysis. As revealed by gene-set enrichment analysis (GSEA) and KEGG pathway enrichment analysis, there was an enrichment of genes involved in JAK-STAT signaling. Further, we observed that the expression of many genes involved in JAK-STAT signaling such as Pdgfb and Pdgfra was significantly increased in Alb-Cre;Prdx1fl/fl mice. Collectively, these results suggest that increased JAK-STAT signaling accounts for the deteriorated NASH phenotypes in Alb-Cre;Prdx1fl/fl mice.
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Project description:Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.
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Project description:Macrophage activation undergoes signal-transduced changes in protein modifications, enabling the coordinated control of transcription and cellular metabolism. However, the role of protein acetylation in signal transduction during macrophage activation remains obscure. Here, we demonstrate that peroxiredoxin 1 (PRDX1), a key regulator of redox signaling, is a novel substrate of the MOF lysine acetyltransferase. Employing a gel based in vitro HAT assay followed by LC-MS, we mapped PRDX1 lysine acetylation sites. PRDX1 K197ac was identified as the most prominent MOF acetylation site. We show that MOF-dependent acetylation of lysine 197 of PRDX1 (PRDX1 K197ac) enhances its peroxidase activity. We find that PRDX1 K197ac is an inflammatory signal-regulated modification, which decreases in mouse macrophages stimulated with bacterial lipopolysaccharides (LPS) but not with IL-4 or IL-10. LPS-induced decrease of PRDX1 K197ac elevates cellular ROS accumulation and augments phosphorylation of ERK1/2 but not p38 or AKT phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Collectively, our findings uncover a regulatory role for redox protein acetylation during inflammatory macrophage activation through modulating signal transduction and coordinating metabolic and transcriptional programs.
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