Inhibition of p53 Sulfoconjugation Prevents Oxidative Hepatotoxicity and Acute Liver Failure,Gastroenterology

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Inhibition of p53 Sulfoconjugation Prevents Oxidative Hepatotoxicity and Acute Liver Failure
Gastroenterology ( IF 25.7 ) Pub Date : 2021-12-23 , DOI: 10.1053/j.gastro.2021.12.260
Pengfei Xu ₁ , Yue Xi ₂ , Pengcheng Wang ₁ , Zigmund Luka ₃ , Meishu Xu ₁ , Hung-Chun Tung ₁ , Jingyuan Wang ₁ , Songrong Ren ₁ , Dechun Feng ₄ , Bin Gao ₄ , Aatur D Singhi ₅ , Satdarshan P Monga ₅ , John D York ₃ , Xiaochao Ma ₁ , Zhiying Huang ₆ , Wen Xie ₇

Affiliation

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 (Papss2^ΔHC) or AAV8-TBG-Cre (Papss2^iΔHC) 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, Papss2^ΔHC 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 Papss2^ΔHC 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.

中文翻译：

抑制 p53 磺基结合可预防氧化性肝毒性和急性肝衰竭

背景与目标

小分子或蛋白肽的磺基结合是确保哺乳动物生化和功能稳态的关键机制。PAPS 合酶 2 (PAPSS2) 是合成通用磺酸盐供体 3'-磷酸腺苷 5'-磷酸硫酸盐 (PAPS) 的主要酶。对乙酰氨基酚 (APAP) 过量是急性肝衰竭 (ALF) 的主要原因，其中氧化应激是关键的致病事件，而 APAP 的硫酸化有助于其解毒。本研究的目的是确定 PAPSS2 是否以及如何在 APAP 诱导的 ALF 中发挥作用。

方法

在患者和小鼠的 APAP 诱导的 ALF 中分析了基因表达。使用 Alb-Cre ( Papss2 ^ΔHC ) 或 AAV8-TBG-Cre ( Papss2 ^iΔHC ) 创建肝脏特异性Papss2基因敲除小鼠，并对其进行 APAP 诱导的 ALF。原代人和小鼠肝细胞用于体外机械分析。

结果

在患者和小鼠的 APAP 诱导的 ALF 中，PAPSS2 的肝脏表达降低。令人惊讶的是，Papss2 ^ΔHC小鼠尽管具有减少的 APAP 硫酸化，但通过激活 p53-p2-Nrf2 轴伴随着增加的肝脏抗氧化能力，因此免受 APAP 诱导的肝毒性。用硫酸化抑制剂治疗也改善了 APAP 诱导的肝毒性。基因敲低实验表明， Papss2 ^ΔHC的保肝作用依赖于 Nrf2、p53 和 p21。从机制上讲，我们将 p53 鉴定为一种新的硫酸化底物。帕普斯2消融通过阻止 p53 硫酸化导致 p53 蛋白积累，从而破坏 p53-MDM2 相互作用和 p53 泛素化并增加 p53 蛋白稳定性。