Redundant and Specific Roles of A-Type Lamins and Lamin B Receptor in Herpes Simplex Virus 1 Infection
Redundant and Specific Roles of A-Type Lamins and Lamin B Receptor in Herpes Simplex Virus 1 Infection
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DOI：
10.1128/jvi.01429-22
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发表时间：
2022-12-21
影响因子：
5.4
通讯作者：
Kawaguchi，Yasushi
中科院分区：
文献类型：
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作者：
Takeshima，Kosuke;Maruzuru，Yuhei;Kawaguchi，Yasushi
我们研究了单纯疱疹病毒（HSV-1）在表达层粘胶蛋白A/C和层粘胶蛋白B受体（LBR）的HeLa细胞感染过程中A型层粘胶蛋白（lamin A/C）和层粘胶蛋白B受体（lamin B receptor， LBR）是否存在冗余。在感染HSV-1的HeLa细胞中，Lamin A/C和LBR双敲除（KO）显著损害了HSV-1早期和晚期基因的表达、复制室的成熟、宿主染色质向核外周的边缘化、宿主细胞核的扩大和病毒DNA的复制。在lamin A/C和LBR双KO细胞中异位表达lamin A/C或LBR可恢复hsv -1感染的HeLa细胞的表型。值得注意的是，层合蛋白A/C单KO，而非LBR单KO，促进了病毒颗粒在内核膜（INM）外的异常积累和病毒复制，并降低了病毒颗粒在内核膜（INM）内的频率，而不影响病毒基因表达和DNA复制、复制室和宿主染色质的时空组织以及核的扩大。这些结果表明，在HSV-1感染过程中，层粘胶蛋白A/C和LBR具有冗余和特异性的作用。因此，核纤层蛋白A/C和LBR冗余调节核结构的动态，包括复制室和宿主染色质的时空组织，以及促进核扩大以实现高效的HSV-1基因表达和DNA复制。相反，lamin A/C在病毒核输出过程中抑制HSV-1核通过INM输出，这是lamin A/C的独特特性。重要意义本研究表明，在HSV-1感染过程中，lamin A/C和LBR通过调控核结构的动态变化，具有与HSV-1基因表达和DNA复制相关的冗余功能。这是首次证实层状蛋白A/C和LBR的冗余作用，以及LBR在hsv -1感染细胞中参与这些病毒和细胞特征的调节。这些发现为层粘胶蛋白A/C抑制HSV-1核出口的特异性提供了证据，这一特性一直被认为但没有直接证据。
We investigated whether A-type lamins (lamin A/C) and lamin B receptor (LBR) are redundant during herpes simplex virus 1 (HSV-1) infection in HeLa cells expressing lamin A/C and LBR. Lamin A/C and LBR double knockout (KO) in HSV-1-infected HeLa cells significantly impaired expressions of HSV-1 early and late genes, maturation of replication compartments, marginalization of host chromatin to the nuclear periphery, enlargement of host cell nuclei, and viral DNA replication. Phenotypes of HSV-1-infected HeLa cells were restored by the ectopic expression of lamin A/C or LBR in lamin A/C and LBR double KO cells. Of note, lamin A/C single KO, but not LBR single KO, promoted the aberrant accumulation of virus particles outside the inner nuclear membrane (INM) and viral replication, as well as decreasing the frequency of virus particles inside the INM without affecting viral gene expression and DNA replication, time-spatial organization of replication compartments and host chromatin, and nuclear enlargement. These results indicated that lamin A/C and LBR had redundant and specific roles during HSV-1 infection. Thus, lamin A/C and LBR redundantly regulated the dynamics of the nuclear architecture, including the time-spatial organization of replication compartments and host chromatin, as well as promoting nuclear enlargement for efficient HSV-1 gene expression and DNA replication. In contrast, lamin A/C inhibited HSV-1 nuclear export through the INM during viral nuclear egress, which is a unique property of lamin A/C.IMPORTANCEThis study demonstrated that lamin A/C and LBR had redundant functions associated with HSV-1 gene expression and DNA replication by regulating the dynamics of the nuclear architecture during HSV-1 infection. This is the first report to demonstrate the redundant roles of lamin A/C and LBR as well as the involvement of LBR in the regulation of these viral and cellular features in HSV-1-infected cells. These findings provide evidence for the specific property of lamin A/C to inhibit HSV-1 nuclear egress, which has long been considered but without direct proof.