Bruton's tyrosine kinase targets NF-kappaB to the bcl-x promoter via a mechanism involving phospholipase C-gamma2 following B cell antigen receptor engagement.
Disruption of Bruton's tyrosine kinase (BTK) function leads to x-linked immunodeficiency (xid) in mice. BTK-deficient (btk(-/-)) B cells are defective for survival. Prior studies show that BTK is required for the induction of Bcl-x(L) following B cell antigen receptor (BCR) engagement. However, the mechanism underlying Bcl-x(L) induction in response to BCR ligation remains unresolved. We now demonstrate that BTK regulates bcl-x expression by transcriptional control in response to BCR engagement. BTK targets nuclear factor-kappaB (NF-kappaB) to activate the bcl-x promoter via a phospholipase C-gamma2 (PLC-gamma2)-dependent mechanism. Perturbation of the BTK/PLC-gamma2/NF-kappaB signaling axis likely contributes to the defective expression of bcl-x and compromised survival of xid B cells.
Petro
James B
JB
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Castro
Iris
I
Lowe
John
J
Khan
Wasif N
WN
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D002645:Chickens; D007527:Isoenzymes / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D051966:Phospholipase C gamma; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015533:Transcriptional Activation; D010738:Type C Phospholipases / Q000502:physiology*; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D007527:Isoenzymes; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D010738:Type C Phospholipases; D051966:Phospholipase C gamma