β1 Integrin Mediates Internalization of Mammalian Reovirus

Abstract

Reovirus infection is initiated by interactions between the attachment protein 1 and cell surface carbohydrate and junctional adhesion molecule A (JAM-A). Expression of a JAM-A mutant lacking a cytoplasmic tail in nonpermissive cells conferred full susceptibility to reovirus infection, suggesting that cell surface molecules other than JAM-A mediate viral internalization following attachment. The presence of integrinbinding sequences in reovirus outer capsid protein 2, which serves as the structural base for 1, suggests that integrins mediate reovirus endocytosis. A ␤1 integrin-specific antibody, but not antibodies specific for other integrin subunits, inhibited reovirus infection of HeLa cells. Expression of a ␤1 integrin cDNA, along with a cDNA encoding JAM-A, in nonpermissive chicken embryo fibroblasts conferred susceptibility to reovirus infection. Infectivity of reovirus was significantly reduced in ␤1-deficient mouse embryonic stem cells in comparison to isogenic cells expressing ␤1. However, reovirus bound equivalently to cells that differed in levels of ␤1 expression, suggesting that ␤1 integrins are involved in a postattachment entry step. Concordantly, uptake of reovirus virions into ␤1-deficient cells was substantially diminished in comparison to viral uptake into ␤1-expressing cells. These data provide evidence that ␤1 integrin facilitates reovirus internalization and suggest that viral entry occurs by interactions of reovirus virions with independent attachment and entry receptors on the cell surface.

NPXY Motifs in the β1 Integrin Cytoplasmic Tail Are Required for Functional Reovirus Entry

“…3A. Although reovirus particles were observed in the cytoplasm of all cell types, there was a notable decrease in ␤1Ϫ/Ϫ cells, as described previously (34). Surprisingly, reovirus particles were internalized into both ␤1ϩ/ϩ and ␤1ϩ/ϩY783F/Y795F cells (Fig.…”

“…All reovirus serotypes bind to proteinaceous receptor junctional adhesion molecule A (JAM-A) to mediate high-affinity attachment (5,14,50). Following receptor binding, reovirus is internalized into cells via a mechanism involving ␤1 integrin (34).…”

Crystal Structure of an Aquabirnavirus Particle: Insights into Antigenic Diversity and Virulence Determinism

“…Taken together, these observations suggest that birnaviruses may need to interact with two different receptors, one for attachment located at the top of the spike-which may confer also tissue tropism and modulate virulence-and a second receptor for internalization, interacting with the conserved groove. This pattern has parallels in other nonenveloped viruses, such as adenoviruses and reoviruses, in which initial attachment to a specific receptor is followed by interaction with an integrin for internalization (37,49). The bottom line of this study is that, in spite of the detailed knowledge of the architecture of the virus particles described here and elsewhere, understanding the underlying birnavirus biology-its entry process and the mechanism of attenuation and virulence-absolutely requires now the identification of the various host partners used for cell invasion.…”

Integrin αvβ1 promotes infection by human metapneumovirus

“…Integrins bind specific ligands in a divalent cation-dependent manner, and a subset of integrins bind to specific recognition sequences such as the amino acid Arg-Gly-Asp (RGD) motif (19). Several viruses use RGD-binding integrins as receptors or co-receptors, including adenovirus (20), echovirus (21), footand-mouth disease virus (22), hantavirus (23), human herpes virus-8 (24), human parechovirus (25), reovirus (26), rotavirus (27), and West Nile virus (28). A role for integrins in infection by any paramyxovirus has not been elucidated.…”