Hepatic steatosis and pyroptosis are induced by the hepatitis B virus X protein via B56α-METTL3 interaction-mediated m6A modification of the NLRP3 mRNA.

IF 9.6 1区 生物学 Q1 CELL BIOLOGY
Ze-Bang Du, Tun Han, Yu-Xin Cai, Yu-Shi Shen, Jia-Shen Wu, Xiong Li, Hang-Tian Zhong, Bai-Heng Wu, Lei Zhang, Liang-Yu Wen, Xiao-Ming Luo, Zhong-Ning Lin, Yu-Chun Lin
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引用次数: 0

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the fastest-growing chronic liver diseases and is characterized by excessive steatosis, inflammation, and progressive liver injury. The hepatitis B virus (HBV) X protein (HBx) is a major viral factor that contributes to the onset and progression of MASH. Emerging evidence highlights the role of epigenetic modifications, particularly N6-methyladenosine (m6A), as prevalent modifications of mRNAs that play crucial roles in MASH pathogenesis by regulating mRNA stability, translation, processing, and nuclear export. However, the epigenetic mechanisms by which m6A modification contributes to HBx-related MASH remain poorly defined. In this study, we observed that NOD-like receptor protein 3 (NLRP3)-dependent pyroptosis and intracellular lipid accumulation are markedly elevated in the livers of HBx-transgenic (HBx-Tg) mice in vivo and in HBx-expressing hepatocytes in vitro, exacerbating liver injury and driving MASH progression. Integrated metabolomic and transcriptomic analyses of HBx-Tg mice revealed distinct gene expression alterations, suggesting a key role for m6A modification in mediating hepatic inflammation and lipotoxicity. Mechanistically, we identified methyltransferase-like 3 (METTL3) as a critical positive regulator of this process. HBx upregulated METTL3 expression and the m6A level of NLRP3 mRNA in HBx-expressing hepatocytes, whereas METTL3 knockdown or catalytic inactivation suppressed NLRP3-dependent pyroptosis. Further investigation revealed that METTL3 enhances NLRP3 mRNA stability via m6A modification at A2748 site in the coding sequence. Moreover, the protein phosphatase 2A (PP2A) B56α subunit was found to interact with the METTL3 methyltransferase domain (MTD), facilitating its enzymatic activity and further increasing NLRP3 m6A methylation, thereby promoting pyroptosis and lipid accumulation in HBx-expressing hepatocytes. Importantly, treatment with STM2457, a selective inhibitor targeting the METTL3 MTD, significantly attenuated hepatic inflammation, steatohepatitis, and lipotoxicity. Taken together, our findings advance the understanding of HBx-induced hepatic lipid accumulation, steatosis, inflammasome formation, and pyroptosis, and indicate that targeting METTL3 with STM2457 intervention is a promising approach for MASH treatment.

乙型肝炎病毒X蛋白通过B56α-METTL3相互作用介导的NLRP3 mRNA的m6A修饰诱导肝脏脂肪变性和焦亡。
代谢功能障碍相关脂肪性肝炎(MASH)是增长最快的慢性肝病之一,其特征是过度脂肪变性、炎症和进行性肝损伤。乙型肝炎病毒(HBV) X蛋白(HBx)是导致MASH发病和进展的主要病毒因子。新出现的证据强调了表观遗传修饰的作用,特别是n6 -甲基腺苷(m6A),作为mRNA的普遍修饰,通过调节mRNA的稳定性、翻译、加工和核输出,在MASH发病机制中起着至关重要的作用。然而,m6A修饰导致hbx相关MASH的表观遗传机制仍不明确。在本研究中,我们观察到在体内hbx转基因(HBx-Tg)小鼠的肝脏和体外表达hbx的肝细胞中,nod样受体蛋白3 (NLRP3)依赖性的焦亡和细胞内脂质积累明显升高,加剧了肝损伤并推动了MASH的进展。HBx-Tg小鼠的综合代谢组学和转录组学分析显示,m6A修饰在介导肝脏炎症和脂肪毒性中起着关键作用。在机制上,我们发现甲基转移酶样3 (METTL3)是这一过程的关键正调节因子。HBx上调表达HBx的肝细胞中METTL3的表达和NLRP3 mRNA的m6A水平,而METTL3敲低或催化失活抑制NLRP3依赖性焦亡。进一步研究发现,METTL3通过编码序列中A2748位点的m6A修饰增强NLRP3 mRNA的稳定性。此外,发现蛋白磷酸酶2A (PP2A) B56α亚基与METTL3甲基转移酶结构域(MTD)相互作用,促进其酶活性,进一步增加NLRP3 m6A甲基化,从而促进hbx表达肝细胞的焦亡和脂质积累。重要的是,STM2457(一种靶向METTL3 MTD的选择性抑制剂)治疗可显著减轻肝脏炎症、脂肪性肝炎和脂肪毒性。综上所述,我们的研究结果促进了对hbx诱导的肝脏脂质积累、脂肪变性、炎性体形成和焦亡的理解,并表明以STM2457干预METTL3是治疗MASH的一种很有前景的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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