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Title: Inhibition of p53 Sulfoconjugation Prevents Oxidative Hepatotoxicity and Acute Liver Failure.

Authors: Xu, Pengfei; Xi, Yue; Wang, Pengcheng; Luka, Zigmund; Xu, Meishu; Tung, Hung-Chun; Wang, Jingyuan; Ren, Songrong; Feng, Dechun; Gao, Bin; Singhi, Aatur D; Monga, Satdarshan P; York, John D; Ma, Xiaochao; Huang, Zhiying; Xie, Wen

Published In Gastroenterology, (2022 Apr)

Abstract: BACKGROUND & AIMS: Sulfoconjugation of small molecules or protein peptides is a key mechanism to ensure biochemical and functional homeostasis in mammals. The PAPS synthase 2 (PAPSS2) is the primary enzyme to synthesize the universal sulfonate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS). Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF), in which oxidative stress is a key pathogenic event, whereas sulfation of APAP contributes to its detoxification. The goal of this study was to determine whether and how PAPSS2 plays a role in APAP-induced ALF. METHODS: Gene expression was analyzed in APAP-induced ALF in patients and mice. Liver-specific Papss2-knockout mice using Alb-Cre (Papss2ΔHC) or AAV8-TBG-Cre (Papss2iΔHC) were created and subjected to APAP-induced ALF. Primary human and mouse hepatocytes were used for in vitro mechanistic analysis. RESULTS: The hepatic expression of PAPSS2 was decreased in APAP-induced ALF in patients and mice. Surprisingly, Papss2ΔHC mice were protected from APAP-induced hepatotoxicity despite having a decreased APAP sulfation, which was accompanied by increased hepatic antioxidative capacity through the activation of the p53-p2-Nrf2 axis. Treatment with a sulfation inhibitor also ameliorated APAP-induced hepatotoxicity. Gene knockdown experiments showed that the hepatoprotective effect of Papss2ΔHC was Nrf2, p53, and p21 dependent. Mechanistically, we identified p53 as a novel substrate of sulfation. Papss2 ablation led to p53 protein accumulation by preventing p53 sulfation, which disrupts p53-MDM2 interaction and p53 ubiquitination and increases p53 protein stability. CONCLUSIONS: We have uncovered a previously unrecognized and p53-mediated role of PAPSS2 in controlling oxidative response. Inhibition of p53 sulfation may be explored for the clinical management of APAP overdose.

PubMed ID: 34954226 Exiting the NIEHS site

MeSH Terms: Acetaminophen/toxicity; Animals; Chemical and Drug Induced Liver Injury*/etiology; Chemical and Drug Induced Liver Injury*/metabolism; Chemical and Drug Induced Liver Injury*/prevention & control; Humans; Liver Failure, Acute*/chemically induced; Liver Failure, Acute*/metabolism; Liver Failure, Acute*/prevention & control; Liver/metabolism; Mammals/metabolism; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2/genetics; NF-E2-Related Factor 2/metabolism; Oxidative Stress; Tumor Suppressor Protein p53/metabolism

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