How do viruses evade detection and clearance? Several strategies are used by viruses ranging from inhibiting antigen processing and presentation to establishing latent or dormant nonreplicative infection. The herpes virus family is particularly adept at both mechanisms. The latent infection established by the herpes virus Epstein-Barr virus (EBV) in B cells is marked by the constitutive expression of the latent membrane protein 2A (LMP2A). LMP2A binds to the Src family kinases Lyn and Syk, and B cells expressing LMP2A exhibit impaired B cell receptor (BCR) activation. Mutation of Tyr112 in LMP2A (Tyr112-LMP2A) prevents Lyn from binding and rescues BCR signaling; however, the mechanism used by LMP2A to block BCR activation is unknown. Dykstra et al. have likely identified how LMP2A subverts BCR function. Wild-type (wt) LMP2A and Tyr112-LMP2A localized to lipid rafts with similar efficiency in transfected B cell lines, indicating that Lyn association was not critical for proper LMP2A membrane targeting. BCR entry into lipid rafts was prevented by cells expressing wt LMP2A, but not by those expressing Tyr112-LMP2A. Antibody-mediated cross-linking of the BCR resulted in accelerated BCR internalization in wt LMP2A- or Tyr112-LMP2A-expressing cell lines; however, in Tyr112-LMP2A-expressing cells, BCR-antigen complexes underwent an accelerated rate of degradation and processing, suggesting that BCR internalization and degradation are mediated separately by LMP2A. These data suggest that LMP2A acts to prevent BCR signaling by blocking BCR translocation to lipid rafts, and blocks BCR-antigen complex degradation and processing. Thus, by preventing B cell activation (by blocking BCR translocation and signaling) and inhibiting the recognition of EBV-infected B cells (by blocking degradation and processing), LMP2A is critical for preventing immune clearance of EBV infection.
M. L. Dykstra, R. Longnecker, S. K. Pierce, Epstein-Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR. Immunity 14, 57-67 (2001). [Online Journal]