Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter via NF-kappaB.
Bruton tyrosine kinase (Btk) is critical for B-cell development. Btk regulates a plethora of signaling proteins, among them nuclear factor-[kappa]B (NF-kappaB). Activation of NF-kappaB is a hallmark of B cells, and NF-kappaB signaling is severely compromised in Btk deficiency. We here present strong evidence indicating that NF-kappaB is required for efficient transcription of the Btk gene. First, we found that proteasome blockers and inhibitors of NF-kappaB signaling suppress Btk transcription and intracellular expression. Similar to Btk, proteasome inhibitors also reduced the expression of other members of this family of kinases, Itk, Bmx, and Tec. Second, 2 functional NF-kappaB-binding sites were found in the Btk promoter. Moreover, in live mice, by hydrodynamic transfection, we show that bortezomib (a blocker of proteasomes and NF-kappaB signaling), as well as NF-kappaB binding sequence-oligonucleotide decoys block Btk transcription. We also demonstrate that Btk induces NF-kappaB activity in mice. Collectively, we show that Btk uses a positive autoregulatory feedback mechanism to stimulate transcription from its own promoter via NF-kappaB.
Yu
Liang
L
Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. liang.yu@ki.se
Mohamed
Abdalla J
AJ
Simonson
Oscar E
OE
Vargas
Leonardo
L
Blomberg
K Emelie M
KE
Björkstrand
Bo
B
Arteaga
H Jose
HJ
Nore
Beston F
BF
Smith
C I Edvard
CI
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001665:Binding Sites; D025461:Feedback, Physiological; D006706:Homeostasis; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D014158:Transcription, Genetic
D016328:NF-kappa B; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D046988:Proteasome Endopeptidase Complex