Inhibition of p53 Sulfoconjugation Prevents Oxidative Hepatotoxicity and Acute Liver Failure.
Inhibition of p53 Sulfoconjugation Prevents Oxidative Hepatotoxicity and Acute Liver Failure.
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DOI：
10.1053/j.gastro.2021.12.260
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发表时间：
2022-04
期刊：
影响因子：
29.4
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Xu P;Xi Y;Wang P;Luka Z;Xu M;Tung HC;Wang J;Ren S;Feng D;Gao B;Singhi AD;Monga SP;York JD;Ma X;Huang Z;Xie W
小分子或蛋白质肽的磺基缀合是确保哺乳动物生物化学和功能稳态的关键机制。PAPS合成酶2（PAPS synthase 2，PAPSS 2）是合成通用磺酸盐供体3′-磷酸腺苷5′-磷酸硫酸酯（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PAPSS 2是否以及如何在APAP诱导的ALF中发挥作用。在患者和小鼠中分析APAP诱导的ALF中的基因表达。使用Alb-Cre（Papss 2 ΔHC）或AAV 8-TBG-Cre（Papss 2 i ΔHC）产生肝脏特异性Papss 2敲除小鼠并使其经受APAP诱导的ALF。原代人和小鼠肝细胞用于体外机制分析。在APAP诱导的ALF中，患者和小鼠的肝脏PAPSS 2表达降低。令人惊讶的是，Papss 2 ΔHC小鼠受到保护，免受APAP诱导的肝毒性，尽管APAP硫酸化降低，这伴随着通过激活p53-p2-Nrf 2轴增加的肝脏抗氧化能力。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，Papss 2 ΔHC的肝保护作用是Nrf 2、p53和p21依赖性的。从机制上讲，我们确定p53作为一种新的硫酸化底物。Papss 2消融通过阻止p53硫酸化导致p53蛋白积聚，这破坏了p53-MDM 2相互作用和p53泛素化，并增加了p53蛋白稳定性。我们已经发现了一个以前未被认识和p53介导的PAPSS 2在控制氧化反应的作用。可以探索抑制p53硫酸化以用于APAP过量的临床管理。抑制硫酸化可以通过激活p53-p21-Nrf 2信号传导轴来预防氧化性肝损伤和急性肝衰竭。
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 is 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. Inhibition of sulfation prevents oxidative liver injury and acute liver failure by activating the p53-p21-Nrf2 signaling axis.
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影响因子：
14.9
作者：
Lee, Tzong-Yi;Huang, Hsien-Da;Hung, Jui-Hung;Huang, Hsi-Yuan;Yang, Yuh-Shyong;Wang, Tzu-Hao
通讯作者：
Wang, Tzu-Hao
影响因子：
13.5
作者：
Ramachandran, Anup;McGill, Mitchell R.;Xie, Yuchao;Ni, Hong-Min;Ding, Wen-Xing;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut
影响因子：
--
作者：
Leung AW;Backstrom I;Bally MB
通讯作者：
Bally MB
影响因子：
3.8
作者：
Kienhuis, Anne S.;van de Poll, Marcel C. G.;van Delft, Joost H. M.
通讯作者：
van Delft, Joost H. M.
影响因子：
12.4
作者：
Jung, S. H.;Lee, H. C.;Lee, J-S
通讯作者：
Lee, J-S