Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD.
B cell homeostasis is regulated by multiple signaling processes, including nuclear factor-kappaB (NF-kappaB), BAFF-, and B cell receptor signaling. Conditional disruption of genes involved in these pathways has shed light on the mechanisms governing signaling from the cell surface to the nucleus. We describe a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLD(ex7/8) mice), which is a deubiquitinating enzyme that is integral to NF-kappaB signaling. This shorter CYLD protein lacks the TRAF2 and NEMO binding sites present in full-length CYLD. A dramatic expansion of mature B lymphocyte populations in all peripheral lymphoid organs occurs in this strain. The B lymphocytes themselves exhibit prolonged survival and manifest a variety of signaling disarrangements that do not occur in mice with a complete deletion of CYLD. Although both the full-length and the mutant CYLD are able to interact with Bcl-3, a predominant nuclear accumulation of Bcl-3 occurs in the CYLD mutant B cells. More dramatic, however, is the accumulation of the NF-kappaB proteins p100 and RelB in CYLD(ex7/8) B cells, which, presumably in combination with nuclear Bcl-3, results in increased levels of Bcl-2 expression. These findings suggest that CYLD can both positively and negatively regulate signal transduction and homeostasis of B cells in vivo, depending on the expression of CYLD splice variants.
Hövelmeyer
Nadine
N
I. Medical Department, Johannes Gutenberg-University Mainz, Verfügungsgebäude, 55131 Mainz, Germany.
Wunderlich
F Thomas
FT
Massoumi
Ramin
R
Jakobsen
Charlotte G
CG
Song
Jian
J
Wörns
Marcus A
MA
Merkwirth
Carsten
C
Kovalenko
Andrew
A
Aumailley
Monique
M
Strand
Dennis
D
Brüning
Jens C
JC
Galle
Peter R
PR
Wallach
David
D
Fässler
Reinhard
R
Waisman
Ari
A
D017398:Alternative Splicing; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D003546:Cysteine Endopeptidases / Q000235:genetics*; D000074749:Deubiquitinating Enzyme CYLD; D053595:Embryonic Stem Cells / Q000276:immunology / Q000502:physiology; D005091:Exons; D005347:Fibroblasts / Q000502:physiology; D014644:Genetic Variation; D006706:Homeostasis; D051379:Mice; D014176:Protein Biosynthesis; D017384:Sequence Deletion; D015398:Signal Transduction
C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases