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PMID: 11489945 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Epstein-Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module.

The Journal of experimental medicine ·Vol. 194 ·No. 3 ·2001-08-06 ·Pages 255-64

Engels N, Merchant M, Pappu R, Chan AC, Longnecker R, Wienands J

Abstract

In latently infected B lymphocytes, the Epstein-Barr virus (EBV) suppresses signal transduction from the antigen receptor through expression of the integral latent membrane protein 2A (LMP2A). At the same time, LMP2A triggers B cell survival by a yet uncharacterized maintenance signal that is normally provided by the antigen receptor. The molecular mechanisms are unknown as LMP2A-regulated signaling cascades have not been described so far. Using a novel mouse model we have identified the intracellular adaptor protein Src homology 2 (SH2) domain-containing leukocyte protein (SLP)-65 as a critical downstream effector of LMP2A in vivo. Biochemical analysis of the underlying signaling pathways revealed that EBV infection causes constitutive tyrosine phosphorylation of one of the two SLP-65 isoforms and complex formation between SLP-65 and the protooncoprotein CrkL (CT10 regulator of kinase like). This leads to antigen receptor-independent phosphorylation of Cbl (Casitas B lineage lymphoma) and C3G. In contrast, phospholipase C-gamma2 (PLC-gamma2) activation is completely blocked. Our data show that in order to establish a latent EBV infection, LMP2A selectively activates or represses SLP-65-regulated signaling pathways.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals B-Lymphocytes/immunology,metabolism,virology Base Sequence Carrier Proteins/chemistry,genetics,metabolism Cell Line DNA Primers/genetics Enzyme Inhibitors/pharmacology Enzyme Precursors/chemistry,metabolism Epstein-Barr Virus Infections/immunology,metabolism,virology Female Herpesvirus 4, Human/metabolism Humans Hydrogen Peroxide/pharmacology Intracellular Signaling Peptides and Proteins Isoenzymes/metabolism Male Mice Mice, Knockout Mice, Transgenic Nuclear Proteins/metabolism Phospholipase C gamma Phosphoproteins/chemistry,genetics,metabolism Phosphorylation Protein Tyrosine Phosphatases/antagonists & inhibitors Protein-Tyrosine Kinases/chemistry,metabolism Signal Transduction Syk Kinase Type C Phospholipases/metabolism Tyrosine/chemistry Vanadates/pharmacology Viral Matrix Proteins/chemistry,genetics,metabolism
Chemicals
Adaptor Proteins, Signal Transducing B cell linker protein CRKL protein Carrier Proteins DNA Primers EBV-associated membrane antigen, Epstein-Barr virus Enzyme Inhibitors Enzyme Precursors Intracellular Signaling Peptides and Proteins Isoenzymes Nuclear Proteins Phosphoproteins Viral Matrix Proteins pervanadate Vanadates Tyrosine Hydrogen Peroxide Protein-Tyrosine Kinases SYK protein, human Syk Kinase Syk protein, mouse Protein Tyrosine Phosphatases Type C Phospholipases Phospholipase C gamma
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Engels N
Department of Biochemistry I, University of Bielefeld, Universitätsstrasse 25, Bielefeld D-33615, Germany.
Merchant M
Pappu R
Chan A C
Longnecker R
Wienands J
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.194.3.255
Published
2001-08-06
Pages
255-64
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193464
Subset
IM
Grants
NCI NIH HHS · CA62234 · United States
NCI NIH HHS · CA73507 · United States
NIDCR NIH HHS · DE13127 · United States
External Links
PubMed source DOI: 10.1084/jem.194.3.255 PMC Full Text View journal details
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