title: Integrin β1 mediates vaccinia virus entry through activation of PI3K/Akt signaling.
abstract: Vaccinia virus has a broad range of infectivity in many cell lines and animals. Although it is known that the vaccinia mature virus binds to cell surface glycosaminoglycans and extracellular matrix proteins, whether additional cellular receptors are required for virus entry remains unclear. Our previous studies showed that the vaccinia mature virus enters through lipid rafts, suggesting the involvement of raft-associated cellular proteins. Here we demonstrate that one lipid raft-associated protein, integrin β1, is important for vaccinia mature virus entry into HeLa cells. Vaccinia virus associates with integrin β1 in lipid rafts on the cell surface, and the knockdown of integrin β1 in HeLa cells reduces vaccinia mature virus entry. Additionally, vaccinia mature virus infection is reduced in a mouse cell line, GD25, that is deficient in integrin β1 expression. Vaccinia mature virus infection triggers the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, and the treatment of cells with inhibitors to block P13K activation reduces virus entry in an integrin β1-dependent manner, suggesting that integrin β1-mediates PI3K/Akt activation induced by vaccinia virus and that this signaling pathway is essential for virus endocytosis. The inhibition of integrin β1-mediated cell adhesion results in a reduction of vaccinia virus entry and the disruption of focal adhesion and PI3K/Akt activation. In summary, our results show that the binding of vaccinia mature virus to cells mimics the outside-in activation process of integrin functions to facilitate vaccinia virus entry into HeLa cells.
authors.affiliation: Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Roza
authors.initials: R
authors.lastname: Izmailyan
authors.forename: Jye-Chian
authors.initials: JC
authors.lastname: Hsao
authors.forename: Che-Sheng
authors.initials: CS
authors.lastname: Chung
authors.forename: Chein-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Paul Wei-Che
authors.initials: PW
authors.lastname: Hsu
authors.forename: Chung-Lin
authors.initials: CL
authors.lastname: Liao
authors.forename: Wen
authors.initials: W
authors.lastname: Chang
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014615:Vaccinia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics / Q000502:physiology*; D053586:Virus Internalization
chemical_list: D019012:Integrin beta1; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt