CYLD is a tumor suppressor that is mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple tumors of the skin appendages. Recent studies suggest that transfected CYLD has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-B. However, the role of endogenous CYLD in regulating cell signaling remains poorly defined. Here we report a critical role for CYLD in negatively regulating the c-Jun NH 2 -terminal kinase (JNK). CYLD

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... by RNA interference results in hyperactivation of JNK by diverse immune stimuli, including tumor necrosis factor-␣, interleukin-1, lipopolysaccharide, and an agonistic anti-CD40 antibody. The JNKinhibitory function of CYLD appears to be specific for immune receptors because the CYLD knockdown has no significant effect on stress-induced JNK activation. Consistently, CYLD negatively regulates the activation of MKK7, an upstream kinase known to mediate JNK activation by immune stimuli. We further demonstrate that CYLD also negatively regulates IB kinase, although this function of CYLD is seen in a receptor-dependent manner. These findings identify the JNK signaling pathway as a major downstream target of CYLD and suggest a receptor-dependent role of CYLD in regulating the IB kinase pathway.