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ERK MAP kinase activated Arf6 trafficking directs CVB3 into an unproductive compartment during virus-host cell entry

University of British Columbia

¹ E-mail: bmcmanus{at}mrl.ubc.ca

Clathrin and caveolae-mediated endocytosis have been implicated in the productive entry of many viruses into host cells. ADP-ribosylation factor (Arf6)-dependent endocytosis is another endocytosis pathway that traffics from the cell surface and it is the only Arf that traffics at the plasma membrane. However, little is known about Arf6-dependent trafficking during virus entry. We show that CVB3 associated with DAF in non-polarised HeLa cells can be redirected into non-productive compartments by Arf6-dependent internalisation, thus restricting infection. Overexpression of wild-type (WT) and constitutively active (CA) Arf6 in HeLa cells resulted in a 2.3 and 3.6-fold decrease in infection, respectively. A dominant negative (DN) inhibitor of Arf6 recovered restriction of infection by WT and CA-Arf6. RNA interference of endogenous Arf6 resulted in a 3.3-fold increase in CVB3 titre in HeLa cells. We show that CAR ligation by virus or CAR-specific antibody can activate Extracellular signal-Regulated Kinase (ERK) of the Mitogen Activated Protein (MAP) kinase family and lead to Arf6-mediated viral restriction. In the absence of ERK activation CVB3 internalisation into early endosomes is inhibited and subsequent infection is reduced, but Arf6-mediated restriction is also abolished. In conclusion, receptor-mediated signalling enhances CVB3 entry while also activating non-productive pathways of virus entry; virus infection is an equilibrium of productive and non-productive pathways of entry.

Received 24 July 2008; accepted 7 December 2008.

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