Herpes Simplex Virus 1 Induces Phosphorylation and Reorganization of Lamin A/C through the γ ₁ 34.5 Protein That Facilitates Nuclear Egress

Abstract

Herpes simplex virus 1 (HSV-1) remodels nuclear membranes during virus egress. Although the UL31 and UL34 proteins control nucleocapsid transit in infected cells, the molecular interactions required for their function are unclear. Here we report that the ␥ 1 34.5 gene product of HSV-1 facilitates nucleocapsid release to the cytoplasm through bridging the UL31/UL34 complex, cellular p32, and protein kinase C. Unlike wild-type virus, an HSV mutant devoid of ␥ 1 34.5 or its amino terminus is crippled for viral growth and release. This is attributable to a defect in virus nuclear egress. In infected cells, wild-type virus recruits protein kinase C to the nuclear membrane and triggers its activation, whereas the ␥ 1 34.5 mutants fail to exert such an effect. Accordingly, the ␥ 1 34.5 mutants are unable to induce phosphorylation and reorganization of lamin A/C. When expressed in host cells ␥ 1 34.5 targets p32 and protein kinase C. Meanwhile, it communicates with the UL31/UL34 complex through UL31. Deletion of the amino terminus from ␥ 1 34.5 disrupts its activity. These results suggest that disintegration of the nuclear lamina mediated by ␥ 1 34.5 promotes HSV replication. IMPORTANCEHSV nuclear egress is a key step that determines the outcome of viral infection. While the nuclear egress complex mediates capsid transit across the nuclear membrane, the regulatory components are not clearly defined in virus-infected cells. We report that the ␥ 1 34.5 gene product, a virulence factor of HSV-1, facilitates nuclear egress cooperatively with cellular p32, protein kinase C, and the nuclear egress complex. This work highlights a viral mechanism that may contribute to the pathogenesis of HSV infection. Herpes simplex virus 1 (HSV-1) replicates and packages its DNA in the cell nucleus. Once assembled, the nucleocapsids traverse the nucleoplasm and cross the nuclear lamina. The capsids bud through the nuclear membranes in a two-step process called envelopment and de-envelopment (1). In this process, the nuclear egress complex, consisting of UL31 and UL34, mediates vesiculation of the inner nuclear membrane and results in enveloped virions in the perinuclear space. Primary virions fuse with the outer nuclear membrane, which releases the capsids to the cytoplasm for further maturation (2). Accumulating evidence suggests that additional proteins, including Us3, ICP22, UL47, gB, and gH, coordinate with the UL31/34 complex to facilitate nuclear egress in infected cells (3-6).The nuclear lamina is a dense meshwork underlying the inner nuclear membrane (7). It is composed primarily of type V intermediate filament proteins, lamin A/C and lamin B. Besides providing structural support to the nucleus, the nuclear lamina potentially presents a barrier to the transit of virus capsids. A number of studies suggest that herpesviruses alter the nuclear lamina to promote nuclear egress (8-11). For example, HSV-1 activates protein kinase C (PKC) isoforms and induces phosphorylation of lamin B, which is dependent on the UL31/UL34 complex (1...

Role of Herpes Simplex Virus 1 γ34.5 in the Regulation of IRF3 Signaling

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Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

“…Given evidence that HSV-1 infected cell protein (ICP) 34.5 is involved in regulation of the interferon system and viral egress (Jing et al, 2004; Wang et al, 2014; Wu et al, 2016), we investigated whether this protein could serve as a viral activator of HPSE. Infection of HCE cells with a mutant virus lacking the γ 34.5 gene was markedly impaired in its ability to upregulate HPSE mRNA expression (Figure 5A).…”

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

“…Conversely, HSV-1 enzymes may also alter the regulation of PTMs on host proteins and histones. For example, HSV-1 UL13 directly phosphorylates host nuclear lamin proteins and this phosphorylation induces partial lamin disassembly or reorganization that allows virions to reach the inner nuclear membranes (16,17). However, even though a prior study identified phosphorylation on HSV-1 proteins (18), a global picture of regulation of host phosphorylation upon HSV-1 infection has not been fully investigated.…”