Prevention of constitutive TNF receptor 1 signaling by silencer of death domains

Tumor necrosis factor receptor type 1 (TNF-R1) contains a cytoplasmic death domain that is required for the signaling of TNF activities such as apopto sis and nuclear factor kappa B (NF-kappa B) activation. Normally, these sig nals are generated only after TNF-induced receptor aggregation. However, TN F-R1 self-associates and signals independently of Ligand when overexpressed . This apparent paradox may be explained by silencer of death domains (SODD ), widely expressed similar to 60-kilodalton protein that was found to be a ssociated with the death domain of TNF-R1. TNF treatment released SODD from TNF-R1, permitting the recruitment of proteins such as TRADD and TRAF2 to the active TNF-R1 signaling complex. SODD also interacted with death recept or-3 (DR3), another member of the TNF receptor superfamily. Thus, SODD asso ciation may be representative of a general mechanism for preventing spontan eous signaling by death domain-containing receptors.