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J. Biol. Chem., Vol. 282, Issue 21, 15884-15893, May 25, 2007

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Deubiquitinating Enzyme CYLD Regulates the Peripheral Development and Naive Phenotype Maintenance of B Cells^*

From the Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

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-B due to spontaneous activation of IB kinase and degradation of the NF-B inhibitor IB. These findings demonstrate a critical role for CYLD in regulating the basal activity of NF-B and maintaining the naive phenotype and proper activation of B cells.

Received for publication, October 24, 2006 , and in revised form, March 27, 2007.

^* This study was supported by National Institutes of Health Grants AI064639 and CA94922 (to S.-C. S.) and an award from the Carlino Account Funds of the Section of Colon and Rectal Surgery, Pennsylvania State College of Medicine (to S.-C. S. and M. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ Both authors contributed equally to this work.

² A recipient of the Ruth L. Kirschstein National Research Service Award.

³ To whom correspondence may be addressed: Dept. of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA. 17033. Tel.: 717-531-4164; Fax: 717-531-6522; E-mail: sxs70{at}psu.edu.

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