ERK MAP kinase-activated Arf6 trafficking directs coxsackievirus type B3 into an unproductive compartment during virus host-cell entry.

Abstract

Clathrin- and caveolae-mediated endocytosis have been implicated in the productive entry of many viruses into host cells. ADP-ribosylation factor 6 (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. This study showed that coxsackievirus type B3 (CVB3) associated with decay-accelerating factor in non-polarized HeLa cells can be redirected into non-productive compartments by Arf6-dependent internalization, 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 inhibitor of Arf6 recovered restriction of infection by WT-Arf6 and CA-Arf6. RNA interference of endogenous Arf6 resulted in a 3.3-fold increase in CVB3 titre in HeLa cells. It was shown that coxsackie-adenovirus receptor (CAR) ligation by virus or CAR-specific antibody could activate extracellular signal-regulated kinase (ERK) of the mitogen-activated protein kinase family and lead to Arf6-mediated viral restriction. In the absence of ERK activation, CVB3 internalization into early endosomes was inhibited and subsequent infection was reduced, but Arf6-mediated restriction was also abolished. In conclusion, receptor-mediated signalling enhances CVB3 entry whilst also activating non-productive pathways of virus entry; thus, virus infection is an equilibrium of productive and non-productive pathways of entry.

• Authors: David Marchant, Alhousseynou Sall, Xiaoning Si, Thomas Abraham, Winnie Wu, Zongshu Luo, Tamar Petersen, Richard G Hegele, Bruce M McManus
• Journal: The Journal of general virology (J Gen Virol) Vol. 90 Issue Pt 4 Pg. 854-862 (Apr 2009) ISSN: 0022-1317 [Print] England
• PMID: 19264606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ADP-Ribosylation Factor 6
• CLMP protein, human
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Receptors, Virus
• Extracellular Signal-Regulated MAP Kinases
• ADP-Ribosylation Factors
• ARF6 protein, human

Topics

• ADP-Ribosylation Factor 6
• ADP-Ribosylation Factors (genetics, metabolism)
• Cell Line
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Endocytosis
• Endosomes (virology)
• Enterovirus B, Human (genetics, metabolism, pathogenicity)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• HeLa Cells
• Humans
• Receptors, Virus (genetics, metabolism)
• Signal Transduction