LMP2A survival and developmental signals are transmitted through Btk-dependent and Btk-independent pathways.
The latent membrane protein 2A (LMP2A) of Epstein--Barr virus (EBV) has been implicated in controlling viral latency due to the ability of LMP2A to block B cell antigen receptor (BCR) signaling in vitro and to alter B cell development and enhance B cell survival in vivo. These LMP2A functions require interactions with the protein tyrosine kinases Syk and Lyn. However, a role for the Bruton's tyrosine kinase (Btk) has not been investigated for these LMP2A functions. To investigate whether Btk is important for LMP2A developmental and survival signals in vivo, LMP2A transgenic animals were mated to Btk deficient (Btk(-/-)) mice. Unlike LMP2A(+), Btk(+/+) transgenic littermate controls, LMP2A(+), Btk(-/-) animals do not generate immunoglobulin (Ig) receptorless B cells in the periphery and instead produce Ig(+) B cells similar to those in the Btk(-/-) mice. Interestingly, however, LMP2A(+), Btk(-/-) animals produce B cells at a vastly reduced level compared to Btk(-/-) littermates, indicating that LMP2A affects B cell development in the absence of Btk. In the RAG-1(-/-), Btk(-/-) double knockout background, LMP2A is still capable of enhancing the survival of Ig-receptorless B cells. Use of Btk phosphopeptide-specific antibodies reveals that Btk is constitutively phosphorylated in LMP2A-expressing cell lines. These data indicate that LMP2A initiates both Btk-dependent and Btk-independent pathways, resulting in altered B cell development and enhanced B cell survival.
Merchant
M
M
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Longnecker
R
R
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018398:Homeodomain Proteins; D014763:Viral Matrix Proteins; C064658:RAG-1 protein; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse