A WEEV 6K viroporin activates MLKL-dependent necroptosis to drive inflammatory injury.

IF 10.4 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2026-07-02 DOI:10.1038/s41420-026-03229-1

Ziyan Zhou, Pengpeng Wu, Zhaobing Gao, Bingqing Xia

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引用次数: 0

Abstract

Neurotropic alphavirus infection is characterized by neuronal injury and sustained neuroinflammation, yet the viral determinants linking membrane perturbation to host inflammatory damage remain poorly defined. Here, we show that the Western equine encephalitis virus (WEEV) 6K protein functions as an ER-localized viroporin, displaying stable single-channel activity with broad cation permeability. Consistent with its ion channel activity, 6K expression perturbs intracellular Ca²⁺ store homeostasis and is associated with cellular injury phenotypes. Mechanistically, 6K predominantly engages MLKL-mediated necroptosis, identifying programmed necrotic signaling as a principal pathway underlying 6K-driven injury under these conditions. Importantly, genetic deletion or pharmacological inhibition of MLKL significantly attenuates 6K-associated cellular damage and inflammatory release, establishing MLKL-dependent execution as a key modifiable node in viroporin-induced host injury. We further identify HYH09-D4 as a protective small molecule that dampens MLKL activation and limits tissue damage associated with 6K expression. Together, these findings define WEEV 6K as a host-facing viroporin that links ionic dysregulation to MLKL-dependent necroptosis and suggest that targeting MLKL may represent a broadly applicable strategy to mitigate host injury driven by 6K-encoding alphaviruses.

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WEEV 6K病毒蛋白激活mlkl依赖性坏死坏死，驱动炎性损伤。

嗜神经型甲病毒感染的特征是神经元损伤和持续的神经炎症，然而连接膜扰动和宿主炎症损伤的病毒决定因素仍然不明确。在这里，我们发现西部马脑炎病毒（WEEV） 6K蛋白作为内质网定位的病毒孔蛋白，具有稳定的单通道活性和广泛的阳离子渗透性。与其离子通道活性一致，6K的表达扰乱了细胞内Ca 2 +的存储稳态，并与细胞损伤表型相关。在机制上，6K主要参与mlkl介导的坏死性坏死，确定程序性坏死信号是这些条件下6K驱动损伤的主要途径。重要的是，基因缺失或药理抑制MLKL可显著减轻6k相关的细胞损伤和炎症释放，从而确立MLKL依赖的执行是病毒孔蛋白诱导的宿主损伤的关键可修改节点。我们进一步发现HYH09-D4是一种保护性小分子，可以抑制MLKL的激活，限制与6K表达相关的组织损伤。总之，这些发现将WEEV 6K定义为一种面向宿主的病毒蛋白，将离子失调与MLKL依赖性坏死坏死联系起来，并表明靶向MLKL可能是一种广泛适用的策略，可以减轻由6K编码阿尔法病毒驱动的宿主损伤。

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 Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.