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