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J Biol Chem. 2007 May 25;282(21):15884-93. Epub 2007 Mar 27.

Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells.

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  • 1Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.

Abstract

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.

PMID:
17392286
DOI:
10.1074/jbc.M609952200
[PubMed - indexed for MEDLINE]
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