Role of the DNA Binding Activity of Herpes Simplex Virus 1 VP22 in Evading AIM2-Dependent Inflammasome Activation Induced by the Virus
Role of the DNA Binding Activity of Herpes Simplex Virus 1 VP22 in Evading AIM2-Dependent Inflammasome Activation Induced by the Virus
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DOI：
10.1128/jvi.02172-20
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发表时间：
2020-12
影响因子：
5.4
通讯作者：
Yuhei Maruzuru;Naoto Koyanagi;Akihisa Kato;Y. Kawaguchi
中科院分区：
文献类型：
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作者：
Yuhei Maruzuru;Naoto Koyanagi;Akihisa Kato;Y. Kawaguchi
VP 22是HSV-1病毒体被膜的主要组分，在α疱疹病毒中是保守的，并且与ORF 52具有结构相似性，ORF 52是病毒体被膜的组分，在γ疱疹病毒中是很保守的。虽然VP 22的潜在DNA结合活性在几十年前就被发现了，但其在HSV-1生命周期中的意义却知之甚少。摘要AIM 2是炎性小体的一个细胞质DNA传感器，它能诱导机体对多种入侵病原体的关键性天然免疫应答。早期的生物化学研究表明，AIM 2与DNA的结合触发了AIM 2的自寡聚化，这对于AIM 2炎性小体激活是必不可少的。我们最近报道，VP 22，一种单纯疱疹病毒1型（HSV-1）的病毒体被膜蛋白，通过阻止AIM 2寡聚化来抑制HSV-1感染细胞中AIM 2炎性小体的激活。VP 22与DNA非特异性结合;然而，它在HSV-1复制中的作用尚不清楚。我们研究了VP 22 DNA结合活性在VP 22介导的AIM 2炎性小体激活抑制中的作用。我们鉴定了包含氨基酸227至258的VP 22结构域作为其体外结合DNA所需的最小结构域。该结构域中的连续丙氨酸取代显著损害了VP 22的体外DNA结合活性，并减弱了VP 22对AIM 2炎性小体重建系统中AIM 2炎性小体活化的抑制作用。VP 22对AIM 2炎性小体激活的抑制作用在用含有VP 22的重组病毒感染的巨噬细胞中完全消除，所述重组病毒具有连续丙氨酸取代之一，类似于VP 22无效突变病毒的作用。这些结果表明，在HSV-1感染的细胞中，VP 22的DNA结合活性对于VP 22介导的AIM 2炎性小体活化是至关重要的。重要性：VP 22是HSV-1病毒体被膜的主要成分，在α疱疹病毒中是保守的，与ORF 52具有结构相似性，ORF 52是病毒体被膜的一种成分，在γ疱疹病毒中是很保守的。虽然VP 22的潜在DNA结合活性在几十年前就被发现了，但其在HSV-1生命周期中的意义却知之甚少。在这里，我们表明VP 22的DNA结合活性对于抑制在HSV-1感染的细胞中诱导的AIM 2炎性小体活化是至关重要的。这是第一份显示VP 22的DNA结合活性在HSV-1生命周期中的作用的报告，允许病毒逃避AIM 2炎性小体激活，这对其体内复制至关重要。
VP22, a major component of the HSV-1 virion tegument, is conserved in alphaherpesviruses and has structural similarity to ORF52, a component of the virion tegument that is well conserved in gammaherpesviruses. Although the potential DNA binding activity of VP22 was discovered decades ago, its significance in the HSV-1 life cycle is poorly understood. ABSTRACT AIM2 is a cytosolic DNA sensor of the inflammasome, which induces critical innate immune responses against various invading pathogens. Earlier biochemical studies showed that the binding of AIM2 to DNA triggered the self-oligomerization of AIM2, which is essential for AIM2 inflammasome activation. We recently reported that VP22, a virion tegument protein of herpes simplex virus 1 (HSV-1), inhibited activation of the AIM2 inflammasome in HSV-1-infected cells by preventing AIM2 oligomerization. VP22 binds nonspecifically to DNA; however, its role in HSV-1 replication is unclear. We investigated the role of VP22 DNA binding activity in the VP22-mediated inhibition of AIM2 inflammasome activation. We identified a VP22 domain comprising amino acids 227 to 258 as the minimal domain required for its binding to DNA in vitro. Consecutive alanine substitutions in this domain substantially impaired the DNA binding activity of VP22 in vitro and attenuated the inhibitory effect of VP22 on AIM2 inflammasome activation in an AIM2 inflammasome reconstitution system. The inhibitory effect of VP22 on AIM2 inflammasome activation was completely abolished in macrophages infected with a recombinant virus harboring VP22 with one of the consecutive alanine substitutions, similar to the effect of a VP22-null mutant virus. These results suggest that the DNA binding activity of VP22 is critical for VP22-mediated AIM2 inflammasome activation in HSV-1-infected cells. IMPORTANCE VP22, a major component of the HSV-1 virion tegument, is conserved in alphaherpesviruses and has structural similarity to ORF52, a component of the virion tegument that is well conserved in gammaherpesviruses. Although the potential DNA binding activity of VP22 was discovered decades ago, its significance in the HSV-1 life cycle is poorly understood. Here, we show that the DNA binding activity of VP22 is critical for the inhibition of AIM2 inflammasome activation induced in HSV-1-infected cells. This is the first report to show a role for the DNA binding activity of VP22 in the HSV-1 life cycle, allowing the virus to evade AIM2 inflammasome activation, which is critical for its replication in vivo.