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SODD-Silencer of Death Domains

R&D Systems, Inc., Minneapolis, Minnesota, USA

Jennifer R. Harrington, Ph.D., R&D Systems, Inc., 614 McKinley Place NE, Minneapolis, Minnesota, USA. Telephone: 612-379-2956; Fax: 612-379-6580; e-mail: info{at}rndsystems.comWebsite http://www.rndsystems.com

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 [1]. In the absence of ligand, DD-containing receptors are maintained in an inactive state.

TNF RI contains a cytoplasmic DD required for signaling pathways associated with apoptosis and NF-B activation [2, 3]. Jiang et al.[4] identified a widely expressed 60 kDa protein, named SODD (silencer of death domains), associated with the DD of TNF RI and DR3. Overexpression of SODD suppresses TNF-induced cell death and NF-B activation demonstrating its role as a negative regulatory protein for these signaling pathways.

TNF-induced receptor trimerization aggregates the DD of TNF RI and recruits the adapter protein TRADD [3, 5]. This in turn promotes the recruitment of the DD-containing cytoplasmic proteins FADD, TRAF2, and RIP to form an active TNF RI signaling complex (Fig. 1A) [6-9]. In contrast, SODD acts as a silencer of TNF RI signaling and does not interact with TRADD, FADD, or RIP (Fig. 1B) [4]. It is associated with the DD of TNF RI and maintains TNF RI in an inactive, monomeric state. TNF-induced aggregation of TNF RI promotes the disruption of the SODD-TNF RI complex.

View larger version (27K): [in this window] [in a new window]   Figure 1. TNF RI initiated apoptosis and activation of NF-B (A) and SODD silencing of TNF RI signaling (B).

References

1. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305-1308.[Abstract/Free Full Text]

2. Tartaglia LA, Ayres TM, Wong GH et al. A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993;74:845-853.[CrossRef][Medline]

3. Hsu H et al. The TNF receptor 1-associated protein YTRADD signals cell death and NF-kappaB activation. Cell 1995;81:495-504.[CrossRef][Medline]

4. Banner DW, D'Arcy A, Janes W et al. Crystal structure of the soluble human SS kd TNF receptor-human TNF beta complex: implications for TNF receptor activation. Cell 1993;73:431-445.[CrossRef][Medline]

5. Banner DW, D'Arcy A, Janes W et al. Crystal structure of the soluble human 55 kd TNF receptor—human TNF-ß complex: implications for TNF receptor activation. Cell 1993;73:431-445.

6. Hsu H, Shu HB, Pan MG et al. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 1996;84:299-308.[CrossRef][Medline]

7. Yeh WC, Pompa JL, McCurrach ME et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 1998;279:1954-1958.[Abstract/Free Full Text]

8. Hsu H, Huang J, Shu HB et al. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 1996;4:387-396.[CrossRef][Medline]

9. Kelliher MA, Grimm S, Ishida Y et al. The death domain kinase RIP mediates the TNF-induced NF-KappaB signal. Immunity 1998;8:297-303.[CrossRef][Medline]

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