| pmid | 10920205 | ||
|---|---|---|---|
| title | T6BP, a TRAF6-interacting protein involved in IL-1 signaling. | ||
| authors |
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| journal | Proc Natl Acad Sci U S A | ||
| year | 2000 | ||
| full_text_available | true | ||
| full_text_extraction_method | html | ||
| pmcid | PMC16905 | ||
| doi | 10.1073/pnas.170279097 |
Authors: Ling L, Goeddel DV Journal: Proc Natl Acad Sci U S A (2000) DOI: 10.1073/pnas.170279097 PMC: PMC16905
- Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9567-72. doi: 10.1073/pnas.170279097.
T6BP, a TRAF6-interacting protein involved in IL-1 signaling.
Ling L(1), Goeddel DV.
Author information: (1)Tularik Inc., South San Francisco, CA 94080, USA.
We report the identification of a TRAF-interacting protein, T6BP, that specifically associates with TRAF6. This interaction occurs between the coiled-coil region of T6BP and the N-terminal ring finger and zinc finger domains of TRAF6. IL-1, but not tumor necrosis factor, induces TRAF6-T6BP complex formation in a ligand-dependent manner. Formation of the TRAF6-T6BP complex depends on the presence of the IL-1 receptor-associated kinase (IRAK). After IL-1 stimulation, TRAF6 can exist in two separate complexes, TRAF6-IRAK or TRAF6-T6BP, but IRAK is not present in TRAF6-T6BP complexes. T6BP does not seem to play a direct role in activation of IkappaB kinases or Jun N-terminal kinase.
DOI: 10.1073/pnas.170279097 PMCID: PMC16905 PMID: 10920205 [Indexed for MEDLINE]
Abstract
We report the identification of a TRAF-interacting protein, T6BP, that specifically associates with TRAF6. This interaction occurs between the coiled-coil region of T6BP and the N-terminal ring finger and zinc finger domains of TRAF6. IL-1, but not tumor necrosis factor, induces TRAF6–T6BP complex formation in a ligand-dependent manner. Formation of the TRAF6–T6BP complex depends on the presence of the IL-1 receptor-associated kinase (IRAK). After IL-1 stimulation, TRAF6 can exist in two separate complexes, TRAF6–IRAK or TRAF6–T6BP, but IRAK is not present in TRAF6–T6BP complexes. T6BP does not seem to play a direct role in activation of IκB kinases or Jun N-terminal kinase.
Discussion
IL-1 is a proinflammatory cytokine that participates in defense response to environmental challenges by generating fever, activating lymphocytes, and promoting infusion of leukocytes into the sites of injury or infection ( 32 ). IL-1 signals through a receptor complex of IL-1RI and the IL-1R accessory protein to generate multiple cellular responses. IL-1 binding to the receptor complex results in the recruitment of the adaptor molecule MyD88 and the serine/threonine kinase IRAK. IRAK becomes autophosphorylated and then interacts with TRAF6, which transduces the IL-1 signal downstream to NF-κB and JNK activation.
In this study, we report the identification of a TRAF6-interacting protein, T6BP. Interestingly, TRAF6 is the only TRAF protein that interacts with T6BP, and this interaction requires the N-terminal ring finger/zinc finger domains of TRAF6. To our knowledge, this is the first case of a TRAF-binding protein that interacts with a single member of the TRAF family specifically through ring finger/zinc finger domains. The ring finger/zinc finger domains of TRAF proteins are thought to be important in transducing signals to downstream targets ( 1 , 4 , 11 , 14 ). Like TRAF proteins, T6BP can also self-associate.
Previously, we identified a protein, MIP-T3, that specifically associates with TRAF3 ( 26 ). TRAF3 dissociates from the TRAF3–MIP-T3 complex and is recruited to the CD40 receptor on CD40 ligand stimulation ( 26 ). Herein, we present another TRAF-binding protein, T6BP, whose interaction with TRAF6 can be induced by IL-1. Identification and characterization of TRAF-binding proteins specific for single members of the TRAF family will be important for understanding the different roles played by individual TRAF proteins.
The association of TRAF6 with T6BP is also different from the interaction of TRAF2 with c-IAP1 ( 33 , 34 ). In TNF receptor signaling, TRAF2 and c-IAP1 are rapidly recruited to both TNFR1 and TNFR2 signaling complexes in a TNF-dependent manner in untransfected mammalian cells ( 34 ). TRAF2 and c-IAP1 are preassociated, and the TRAF2–c-IAP1 complex interacts with TNFR2 via TRAF2 ( 33 , 34 ), whereas the recruitment of TRAF2 and c-IAP1 to TNFR1 is mediated by TRADD ( 13 , 34 ). In the case of IL-1 receptor signaling, IRAK, not TRAF6, is recruited to the activated receptors. IRAK becomes highly phosphorylated and then forms a complex with TRAF6 that is not associated with the IL-1 receptor.
Our results suggest that IRAK is required for IL-1-induced TRAF6–T6BP complex formation. Like TRAF6, IRAK has been shown both biochemically and genetically to be essential for NF-κB and JNK activation by IL-1 ( 35 – 37 ). It is tentative to place TRAF6–T6BP complex downstream of TRAF6–IRAK complex. It can be postulated that only “modified” TRAF6, either aggregated or phosphorylated by IRAK, is therefore capable of interacting with T6BP.
Although gene targeting data in mice suggest that TRAF6 is also important in CD40 signaling, CD40 ligand does not induce the TRAF6–T6BP complex formation. These results agree well with the requirement for IRAK in TRAF6–T6BP complex formation. In CD40 signaling, TRAF6 is directly recruited to the activated receptor, bypassing the dependence on IRAK of the IL-1 pathway ( 11 ). It will be interesting to investigate whether activation of IL-18 or Toll signaling pathways induces the interaction between TRAF6 and T6BP, because IRAK is implicated in these pathways ( 38 , 39 ).
TRAF6 is essential for NF-κB and JNK activation by IL-1. However, T6BP neither activates nor inhibits either of these two pathways in transient transfection experiments (Fig. 9 and data not shown). These results provide clues for bifurcation of the NF-κB/JNK pathways and other pathways at the level of TRAF6. Additional efforts will be required to determine the specific functional roles of the T6BP–TRAF6 complex in IL-1 signaling and of T6BP in other pathways.