A classical anti-autophagic viral protein reshapes mitochondria for immune evasion.

IF 14.3

Autophagy Pub Date : 2025-06-30 DOI:10.1080/15548627.2025.2522130

Qing Zhu, Chengyu Liang

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Abstract

Viral subversion of macroautophagy/autophagy is a well-established immune evasion strategy, with BCL2 homologs from γ-herpesviruses serving as prototypical inhibitors through BECN1 (beclin 1) sequestration. Yet the full spectrum of their functions remains incompletely understood. In our recent study, we uncovered a non-canonical role for the Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded BCL2 homolog (vBCL2) during late lytic replication. Unexpectedly, vBCL2 hijacks the host NDP kinase NME2/NM23-H2 to activate the mitochondrial fission GTPase DNM1L/DRP1, promoting mitochondrial fragmentation. This organelle remodeling dismantles MAVS-mediated antiviral signaling and facilitates virion assembly. A vBCL2 mutant unable to bind NME2 fails to induce fission or complete the viral lifecycle. These findings provide a long-sought answer to why vBCL2 is indispensable during lytic infection, and uncover a new immune evasion strategy centered on mitochondrial control. Our work expands the current view of virus-organelle interactions beyond canonical autophagy control and offers new targets for therapeutic intervention.

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一种经典的抗自噬病毒蛋白重塑线粒体以逃避免疫。

病毒破坏巨噬/自噬是一种成熟的免疫逃避策略，来自γ-疱疹病毒的BCL2同源物通过BECN1 （beclin 1）隔离充当原型抑制剂。然而，它们的全部功能仍未被完全了解。在我们最近的研究中，我们发现了卡波西肉瘤相关疱疹病毒（KSHV）编码的BCL2同源物（vBCL2）在后期裂解复制中的非规范作用。出乎意料的是，vBCL2劫持宿主NDP激酶NME2/NM23-H2，激活线粒体裂变GTPase DNM1L/DRP1，促进线粒体断裂。这种细胞器重塑破坏了mavs介导的抗病毒信号，促进了病毒粒子的组装。不能结合NME2的vBCL2突变体不能诱导裂变或完成病毒生命周期。这些发现为为什么vBCL2在溶解性感染中不可或缺提供了一个长期寻求的答案，并揭示了一种以线粒体控制为中心的新的免疫逃避策略。我们的工作扩展了目前关于病毒-细胞器相互作用的观点，超越了典型的自噬控制，并为治疗干预提供了新的靶点。

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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Autophagy

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