title: 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.
  
  
  OBJECTIVE
  The actin cytoskeleton is involved in many crucial cellular processes and acts as an obstacle to pathogen entry into host cells. Because HSV-1 establishes lifelong latency in neurons and because neuronal cytoskeletal disruption is thought to be the main cause of HSV-1-induced neurodegeneration, understanding the F-actin remodeling pattern by HSV-1 infection and the molecular interactions that facilitate HSV-1 entry into neurons is important. In this study, we showed that HSV-1 infection induces the rearrangement of the cytoskeleton as well as the initial inactivation and subsequent activation of cofilin. Then, we determined that activation of the EGFR-PI3K-Erk1/2 signaling pathway inactivates cofilin and promotes F-actin polymerization. We postulate that by regulating actin cytoskeleton dynamics, cofilin biphasic activation could represent the specific cellular machinery usurped by pathogen infection, and these results will greatly contribute to the understanding of HSV-1-induced early and complex changes in host cells that are closely linked to HSV-1 pathogenesis.
authors.forename: Kai
authors.initials: K
authors.lastname: Zheng
authors.forename: Yangfei
authors.initials: Y
authors.lastname: Xiang
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Wang
authors.forename: Meigong
authors.initials: M
authors.lastname: Zhong
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Jianglin
authors.initials: J
authors.lastname: Fan
authors.forename: Kaio
authors.initials: K
authors.lastname: Kitazato
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009474:Neurons / Q000821:virology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D053586:Virus Internalization
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors