the tumor suppressor cyld interacts with trip and regulates negatively nuclear factor kappab activation by tumor necrosis factor cylindromas are benign adnexal skin tumors caused by germline mutations in the cyld gene in most cases the second wildtype allele is lost in tumor tissue suggesting that cyld functions as tumor suppressor cyld is a protein of 956 amino acids harboring a functional deubiquitinating domain at the coohterminal end to shed more light on the function of cyld we have performed a yeast two hybrid screen using an hacat cdna library that identified the ring finger protein trip trafinteracting protein as interactor with fulllength cyld mapping of the interacting domains revealed that the central domain of cyld binds to the coohterminal end of trip far western analysis and coimmunoprecipitations in mammalian cells confirmed that fulllength cyld binds to the coohterminal domain of trip because trip is an inhibitor of nuclear factor nfkappab activation by tumor necrosis factor tnf the effect of cyld on nfkappab activation was investigated in hela cells the results established that cyld downregulates nfkappab activation by tnfalpha the inhibition by cyld depends on the presence of the central domain interacting with trip and its deubiquitinating activity these findings indicate that cylindromas arise through constitutive nfkappab activation leading to hyperproliferation and tumor growth