Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells.
Deubiquitinating enzymes (DUB) form a family of cysteine proteases that digests ubiquitin chains and reverses the process of protein ubiquitination. Despite the identification of a large number of DUBs, their physiological functions remain poorly defined. Here we provide genetic evidence that CYLD, a recently identified DUB, plays a crucial role in regulating the peripheral development and activation of B cells. Disruption of the CYLD gene in mice results in B cell hyperplasia and lymphoid organ enlargement. The CYLD-deficient B cells display surface markers indicative of spontaneous activation and are hyperproliferative upon in vitro stimulation. When challenged with antigens, the CYLD(-/-) mice develop exacerbated lymphoid organ abnormalities and abnormal B cell responses. Although the loss of CYLD has only a minor effect on B cell development in bone marrow, this genetic deficiency disrupts the balance of peripheral B cell populations with a significant increase in marginal zone B cells. In keeping with these functional abnormalities, the CYLD(-/-) B cells exhibit constitutive activation of the transcription factor NF-kappaB due to spontaneous activation of IkappaB kinase beta and degradation of the NF-kappaB inhibitor IkappaBalpha. These findings demonstrate a critical role for CYLD in regulating the basal activity of NF-kappaB and maintaining the naive phenotype and proper activation of B cells.
Jin
Wei
W
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Reiley
William R
WR
Lee
Andrew J
AJ
Wright
Ato
A
Wu
Xuefeng
X
Zhang
Minying
M
Sun
Shao-Cong
SC
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009929:Organ Size / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism
D000943:Antigens, Differentiation; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases