Inhibition of p53 Sulfoconjugation Prevents Oxidative Hepatotoxicity and Acute Liver Failure

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 162; no. 4; pp. 1226 - 1241
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2022
• Subjects: Acetaminophen; 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 - metabolism; Liver Failure, Acute - chemically induced; Liver Failure, Acute - metabolism; Liver Failure, Acute - prevention & control; Mammals - metabolism; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Hepatotoxicity; Oxidative Stress; p53; PAPSS2; Sulfation; Tumor Suppressor Protein p53 - metabolism; APAP; PQ; ALT; mRNA; Oxidative Hepatotoxicity; ChIP; PAPSS2; p53; PAPS; scRNA-seq; shRNA; PAPSS; Cys; GSH; WT; GSSG; AST; Tyr; Sulfation; NAC; Acetaminophen; TAA; ROS; ALF; CYP2E1; Mer; NAPQI; PCR
• DOI: 10.1053/j.gastro.2021.12.260
• ISSN: 0016-5085

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. 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. 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. 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. [Display omitted] Inhibition of sulfation prevents oxidative liver injury and acute liver failure by activating the p53-p21-Nrf2 signaling axis.