Epidermal Growth Factor Receptor-PI3K Signaling Controls Cofilin Activity To Facilitate Herpes Simplex Virus 1 Entry into Neuronal Cells

Abstract

Herpes simplex virus type 1 (HSV-1) establishes latency in neurons and can cause severe disseminated infection with neurological impairment and high mortality. This neurodegeneration is thought to be tightly associated with virus-induced cytoskeleton disruption. Currently, the regulation pattern of the actin cytoskeleton and the involved molecular mechanisms during HSV-1 entry into neurons remain unclear. Here, we demonstrate that the entry of HSV-1 into neuronal cells induces biphasic remodeling of the actin cytoskeleton and an initial inactivation followed by the subsequent activation of cofilin, a member of the actin depolymerizing factor family that is critical for actin reorganization. The disruption of F-actin dynamics or the modulation of cofilin activity by mutation, knockdown, or overexpression affects HSV-1 entry efficacy and virus-mediated cell ruffle formation. Binding of the HSV-1 envelope initiates the epidermal growth factor receptor (EGFR)-phosphatidylinositide 3-kinase (PI3K) signaling pathway, which leads to virus-induced early cofilin phosphorylation and F-actin polymerization. Moreover, the extracellular signal-regulated kinase (ERK) kinase and Rho-associated, coiled-coil-containing protein kinase 1 (ROCK) are recruited as downstream mediators of the HSV-1-induced cofilin inactivation pathway. Inhibitors specific for those kinases significantly reduce the virus infectivity without affecting virus binding to the target cells. Additionally, lipid rafts are clustered to promote EGFR-associated signaling cascade transduction. We propose that HSV-1 hijacks cofilin to initiate infection. These results could promote a better understanding of the pathogenesis of HSV-1-induced neurological diseases.

Equine Herpesvirus Type 1 Enhances Viral Replication in CD172a + Monocytic Cells upon Adhesion to Endothelial Cells

“…Together, these data show that integrin engagement and the activation of integrin-mediated signaling pathways are essential in the induction of EHV-1-infected CD172a ϩ adhesion to EC. Several herpesviruses, such as pseudorabies virus (PRV), herpes simplex virus 1 (HSV-1), human herpesvirus 8 (HHV-8), and HCMV, have been reported to activate integrin-mediated ERK-MAPK and PI3K signaling pathways through the interactions of viral glycoproteins with putative receptors present at the plasma membranes of host cells (23,28,(33)(34)(35). To date, the EHV-1 envelope glycoprotein D (gD) has been shown to interact with ␣V integrins present on PBMC and to be critical for viral entry via endocytosis (36).…”

Cofilin-1 is involved in regulation of actin reorganization during influenza A virus assembly and budding

“…Cofilin-1 is deactivated by phosphorylation on Ser-3 by LIM-kinase1 (LIMK1), and results in an increase in F-actin [35,36]. Disruption of the LIMK1-cofilin pathway affected viral releases of Mason-Pfizer monkey virus (M-PMV) and HIV-1 [21], as well as the entry and replication of HSV-1 [22,23,24]. However, there are no reports on IAV.…”

“…IAV infection results in activation of phosphoinositide 3-kinase (PI3K) signaling pathway, which may inactivates cofilin and promote F-actin polymerization [23,37,38]. It has been reported that PGG reduces the expression of PI3K as well as phosphorylation of AKT and mammalian target of rapamycin (mTOR) [39].…”

“…HIV-1 inactivates cofilin to optimize immune evasion, replication, release, and cell-cell transmission [19,20,21]. We have previously reported that cofilin-1 play a crucial role in mediating biphasic F-actin dynamics to facilitate HSV-1 infection and replication [22,23]. Cofilin-1 mediates the inhibition of actincytoskeleton remodeling and the anti-HSV activity of pentagalloyl glucose (PGG) [24].…”

Differential regulation of astrocyte prostaglandin response by kinins: Possible role for mitogen activated protein kinases

“…U-0126 inhibited the active phosphorylated form of mitogen activated MAPK kinase (MEK1) specifically, with IC 50 value of 10 μM. In cell models including astrocytes, concentrations of U-0126 shown to be effective range from 1 to 20 μM (Lim et al, 2007, Zheng et al 2014, Moore et al, 2013. For complete inhibition of MEK1, U-0126 (20 μM) was used.…”