Abstract
Viruses utilize host cell signaling to facilitate productive infection. Equine herpesvirus type 1 (EHV-1) has been shown to activate Ca2+ release and phospholipase C upon contact with α4β1 integrins on the cell surface. Signaling molecules, including small GTPases, have been shown to be activated downstream of Ca2+ release, and modulate virus entry, membrane remodeling and intracellular transport. In this study, we show that EHV-1 activates the small GTPases Rac1 and Cdc42 during infection. The activation of Rac1 and Cdc42 is necessary for virus-induced acetylation of tubulin, effective viral transport to the nucleus, and cell-to-cell spread. We also show that inhibitors of Rac1 and Cdc42 did not block virus entry, but inhibited overall virus infection. The Rac1 and Cdc42 signaling is presumably orthogonal to Ca2+ release, since Rac1 and Cdc42 inhibitors affected the infection of both EHV-1 and EHV-4, which do not bind to integrins.
Highlights
Cellular functions are governed by complex signaling networks, and regulation is achieved by countless molecules, most of which are proteins [1]
We identified that Rac1 and Cdc42 small GTPases activation is required for the intracellular transport of Equine herpesvirus type 1 (EHV-1) through the acetylation of microtubules
EHV-1 strain RacL11 (L11-RFP), expressing red fluorescent protein (RFP), fused to the small capsid protein VP26 [15], EHV-1 gH4 [19]—EHV-1 expressing gH from EHV-4 that cannot bind to α4β1 integrins (L11-gH4), EHV-1 gHS440A [19] that harbors 3 amino acid substitutions in the gH-integrin binding motif that renders the virus unable to bind to α4β1 integrins, and the EHV-4 strain TH20p [20] was used in this study
Summary
Cellular functions are governed by complex signaling networks, and regulation is achieved by countless molecules, most of which are proteins [1]. EHV-1 is able to induce signal transduction inside the infected cell that leads to the activation of phospholipase C, the release of inositol triphosphate, Ca2+ release from endoplasmic reticulum, after interaction with α4β1-integrins on the surface of the cells This signaling cascade is necessary for fusion at the plasma membrane [15]; the exact mechanism that facilitates virus entry is still unknown. Small GTPases were described to be activated downstream of Ca2+ release, and are involved in cellular processes such as cytoskeleton remodeling, membrane fusion and intracellular transport These properties make small GTPases a good candidate to further investigate the signaling cascade induced by EHV-1 [16,17,18]. We identified that Rac and Cdc small GTPases activation is required for the intracellular transport of EHV-1 through the acetylation of microtubules
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