Health / Medical Topics

    SODD/TNFR1 Signaling Pathway

    The tumor necrosis factor (TNF) receptor superfamily contains several members with homologous cytoplasmic domains known as death domains (DD). The intracellular DD are important in initiating apoptosis and other signaling pathways following ligand binding by the receptors. In the absence of ligand, DD-containing receptors are maintained in an inactive state. TNFR1 contains a cytoplasmic DD required for signaling pathways associated with apoptosis and NF-kB activation. Jiang et al. identified a widely expressed 60 kDa protein, named SODD (silencer of death domains), associated with the DD of TNFR1 and DR3. Overexpression of SODD suppresses TNF-induced cell death and NF-kB activation demonstrating its role as a negative regulatory protein for these signaling pathways. TNF-induced receptor trimerization aggregates the DD of TNFR1 and recruits the adapter protein TRADD. This in turn promotes the recruitment of the DD-containing cytoplasmic proteins FADD, TRAF2, and RIP to form an active TNFR1 signaling complex. In contrast, SODD acts as a silencer of TNFR1 signaling and does not interact with TRADD, FADD, or RIP. It is associated with the DD of TNFR1 and maintains TNFR1 in an inactive, monomeric state. TNF-induced aggregation of TNFR1 promotes the disruption of the SODD-TNFR1 complex. SODD does not interact with the DD of other TNF receptor superfamily members such as Fas, DR4, DR5, or TNFR2. SODD association with TNFR1 may represent a general model for the prevention of spontaneous TNF signaling by other DD-containing receptors. (NCI Thesaurus/BIOCARTA)




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