Abstract
BackgroundCytoskeletal proteins are often involved in the virus life cycle, either at early steps during virus entry or at later steps during formation of new virus particles. Though actin filaments have been shown to play a role in the production of measles virus (MV), the importance of actin dynamics for virus assembly and budding steps is not known yet. Aim of this work was thus to analyze the distinctive consequences of F-actin stabilization or disruption for MV protein trafficking, particle assembly and virus release.ResultsMV infection studies in the presence of inhibitors differently affecting the actin cytoskeleton revealed that not only actin disruption but also stabilization of actin filaments interfered with MV particle release. While overall viral protein synthesis, surface expression levels of the MV glycoproteins, and cell-associated infectivity was not altered, cell-free virus titers were decreased. Interestingly, the underlying mechanisms of interference with late MV maturation steps differed principally after F-actin disruption by Cytochalasin D (CD) and F-actin stabilization by Jasplakinolide (Jaspla). While intact actin filaments were shown to be required for transport of nucleocapsids and matrix proteins (M-RNPs) from inclusions to the plasma membrane, actin dynamics at the cytocortex that are blocked by Jaspla are necessary for final steps in virus assembly, in particular for the formation of viral buds and the pinching-off at the plasma membrane. Supporting our finding that F-actin disruption blocks M-RNP transport to the plasma membrane, cell-to-cell spread of MV infection was enhanced upon CD treatment. Due to the lack of M-glycoprotein-interactions at the cell surface, M-mediated fusion downregulation was hindered and a more rapid syncytia formation was observed.ConclusionWhile stable actin filaments are needed for intracellular trafficking of viral RNPs to the plasma membrane, and consequently for assembly at the cell surface and prevention of an overexerted fusion by the viral surface glycoproteins, actin dynamics are required for the final steps of budding at the plasma membrane.
Highlights
Cytoskeletal proteins are often involved in the virus life cycle, either at early steps during virus entry or at later steps during formation of new virus particles
With our studies on measles virus (MV) replication in the presence of Cytochalasin D (CD) and Jaspla, we show that defects in actin polymerisation and defects in actin depolymerisation can both interfere with late virus assembly and budding steps without impairing overall viral protein synthesis, cell-associated infectivity or the surface transport of the MV glycoproteins
Actin disruption and stabilization affect virus release without influencing the amount of cell-associated infectivity To analyze the importance of the actin polymerization and depolymerization on MV infection, we quantitated the release of infectious MV particles and the cellassociated infectivity in the absence and presence of 4 μM Cytochalasin D (CD) or 100 nM Jasplakinolide (Jaspla)
Summary
Cytoskeletal proteins are often involved in the virus life cycle, either at early steps during virus entry or at later steps during formation of new virus particles. The actin network is primarily associated with mechanical stability, cell motility and cell contraction. It is important for chromosome movement during mitosis and for internal transport, near the plasma membrane. For MV, several reports have shown that actin is involved in virus maturation at the plasma membrane. This idea was initially based on the findings that actin was identified as an internal component of MV particles [8,9] and co-caps with MV H on infected cells [10]. It was proposed that F-actin associates with the MV M protein altering the interaction between M and H, hereby modulating MV cell-cell fusion and assembly [11]
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