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Journal of Virology, May 2003, p. 5529-5534, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5529-5534.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Itchy, a Nedd4 Ubiquitin Ligase, Downregulates Latent Membrane Protein 2A Activity in B-Cell Signaling

Akiko Ikeda, Robert G. Caldwell,{dagger} Richard Longnecker,* and Masato Ikeda

Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611

Received 11 October 2002/ Accepted 21 January 2003

Nedd4 family ubiquitin protein ligases (E3s) specifically associate with latent membrane protein 2A (LMP2A) of Epstein-Barr virus. Our previous studies analyzing LMP2A function in vitro have suggested that Nedd4 family E3s regulate LMP2A function. To determine the role of Nedd4 family E3s in LMP2A B-cell signaling, LMP2A transgenic (LMP2A+) mice were crossed with mice with the Itch-deficient (Itch-/-) background. Itchy, a mouse homologue of human AIP4, is a Nedd4 family E3 and is also the most abundant Nedd4 family E3 found in LMP2A affinity precipitates from B cells. There were significantly fewer B-cell receptor-positive B cells in spleen and bone marrow B cells in LMP2A+ Itch-/- mice than in LMP2A+ mice. In addition, LMP2A+ Itch-/- bone marrow B cells formed larger colonies in cultures treated with interleukin-7 (IL-7) than control bone marrow B cells did. Finally, there was a dramatic increase in tyrosine phosphorylation of LMP2A and Syk in IL-7-cultured LMP2A+ Itch-/- B cells. These results indicate that Nedd4 family E3s, in particular Itchy, downmodulate LMP2A activity in B-cell signaling.

* Corresponding author. Mailing address: Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611. Phone: (312) 503-0467. Fax: (312) 503-1339. E-mail: r-longnecker{at}northwestern.edu.

{dagger} Present address: Covance Laboratories, Madison, WI 53704.

Journal of Virology, May 2003, p. 5529-5534, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5529-5534.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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