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.