The viral BCL2 protein BHRF1 of Epstein-Barr virus promotes AIM2 inflammasome activation to facilitate lytic replication.

IF 4.9 1区医学 Q1 MICROBIOLOGY

PLoS Pathogens Pub Date : 2025-09-22 eCollection Date: 2025-09-01 DOI:10.1371/journal.ppat.1013509

Qingping Lan, Xiaolin Zhang, Yifan Sun, Jing Yang, Xiaojuan Li, Ersheng Kuang

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引用次数: 0

Abstract

The absent in melanoma 2 (AIM2) protein recognizes viral and naked dsDNA and recruit apoptosis-associated speck-like protein containing CARD (ASC) to initiate inflammasome activation; however, the subversion of AIM2 activation by Epstein-Barr virus (EBV) infection remains unknown. Here, we reveal that the EBV-encoded viral BCL2 protein BHRF1 promotes AIM2 inflammasome activation. The BHRF1 C-terminal domain binds to AIM2 HIN domain and directly promotes dsDNA recognition and AIM2-ASC interaction, consequently cooperates with viral dsDNA to enable inflammasome activation. The single-site mutations R162A and F164A in BHRF1 and E186A in AIM2 abolish their interaction and AIM2 inflammasome activation. BHRF1 recruits AIM2 inflammasome to the mitochondrial compartment and facilitates EBV lytic replication through KAP1 and GSDMD cleavage. BHRF1 deficiency strongly decreases AIM2 inflammasome activation and EBV lytic replication, and reintroduction of wild-type BHRF1 but not the BHRF1 R162A or F164A mutant restores these functions. These results suggest that BHRF1 protein directly promotes the AIM2 inflammasome activation in the mitochondrial compartment to facilitate lytic replication.

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eb病毒的病毒BCL2蛋白BHRF1促进AIM2炎性小体的激活，促进裂解复制。

黑色素瘤2中缺失蛋白（AIM2）识别病毒和裸dsDNA，并招募含有CARD的凋亡相关斑点样蛋白（ASC）启动炎性体激活；然而，eb病毒（EBV）感染对AIM2激活的破坏尚不清楚。在这里，我们发现ebv编码的病毒BCL2蛋白BHRF1促进AIM2炎性体的激活。BHRF1 c端结构域结合AIM2 HIN结构域，直接促进dsDNA识别和AIM2- asc相互作用，从而与病毒dsDNA协同激活炎性小体。BHRF1中的R162A和F164A以及AIM2中的E186A的单位点突变使它们的相互作用和AIM2炎性体的激活失效。BHRF1将AIM2炎性体招募到线粒体室，并通过KAP1和GSDMD裂解促进EBV裂解复制。BHRF1缺乏强烈降低AIM2炎性体的激活和EBV裂解复制，重新引入野生型BHRF1而不是BHRF1 R162A或F164A突变体恢复这些功能。这些结果表明，BHRF1蛋白直接促进线粒体室中AIM2炎性体的激活，促进裂解复制。

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来源期刊

PLoS Pathogens MICROBIOLOGY-PARASITOLOGY

自引率

3.00%

发文量

598

期刊介绍： Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.