Distinct molecular mechanism for initiating TRAF6 signalling

Ye, Hong; Arron, Joseph R.; Lamothe, Betty; Cirilli, Maurizio; Kobayashi, Takashi; Shevde, Nirupama K.; Segal, Deena; Dzivenu, Oki K.; Vologodskaia, Masha; Yim, Mijung; Du, Khoi; Singh, Sujay; Pike, J. Wesley; Darnay, Bryant G.; Choi, Yongwon; Wu, Hao

doi:10.1038/nature00888

Cited by 608 publications

(681 citation statements)

References 30 publications

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“…5 CD40 signaling through tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) suggests that CD40 is a major component of the crosstalk between the TNF receptor superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. [6][7][8] In activated DC, these pathways are essential for NF-kB-dependent IL-12 synthesis, a central cytokine bridging innate and adaptive immunity. 9 In addition to APCs, CD40 is constitutively expressed on a broad array of cells with high proliferative potential, including endothelium, some epithelial cells, and certain tumors.…”

mentioning

confidence: 99%

Immune properties of recombinant vaccinia virus encoding CD154 (CD40L) are determined by expression of virally encoded CD40L and the presence of CD40L protein in viral particles

Bereta

Park

et al. 2004

Cancer Gene Ther

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Expression of costimulatory molecules by recombinant poxviruses is a promising strategy for enhancing therapeutic vaccines. CD40-CD40L interactions are critical for conditioning dendritic cells (DC) and priming T-and B-cell immunity. We constructed a vaccinia virus expressing murine CD40L (rV-CD40L) and studied its immunomodulatory properties in vitro. Direct DC infection with control vaccinia or psoralen/UV-inactivated rV-CD40L stimulated high levels of interleukin 12 (IL-12) release. However, replication-competent rV-CD40L did not stimulate IL-12 under similar conditions. We observed a high level of CD40L protein on purified viral particles and demonstrated that induction of IL-12 by nonreplicating rV-CD40L was blocked by anti-CD40 antibodies suggesting that functional CD40L on viral particles contributed to alterations in IL-12 synthesis.Since cross-presentation of tumor-associated antigens by DC is augmented by viral infection of tumor cells, we infected MC38 murine colon carcinoma cells with rV-CD40L. Infected cells stimulated IL-12 secretion by DC and proliferation of B cells and DX5 þ (NK/NKT) cells through direct CD40-CD40L interaction. A subpopulation of NKT cells expressing CD40 (NK1.1 þ , CD3 lo ) appeared to be a major effector population responding to MC38/rV-CD40L. These results highlight the complex immune regulatory effects of rV-CD40L defined by the cumulative effects of CD40L expression, presence of CD40L protein in viral particles, and the replication potential of the virus.

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mentioning

confidence: 99%

Immune properties of recombinant vaccinia virus encoding CD154 (CD40L) are determined by expression of virally encoded CD40L and the presence of CD40L protein in viral particles

Bereta

Park

et al. 2004

Cancer Gene Ther

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“…TRAF family proteins contain a conserved TRAF-C domain that is essential for the interaction with their cognate receptors or cytoplasmic signaling proteins (13)(14)(15)(16). Among TRAF family proteins, TRAF6 exhibits the unique properties in that its TRAF-C domain interacts with a peptide motif distinct from that recognized by other TRAF proteins (17), supporting the findings that TRAF6 exhibits various functions in regulating adaptive and innate immunity, bone metabolism, and cell apoptosis (13)(14)(15)(16). The structural analysis of the peptide-TRAF6 interaction has clarified the TRAF6-binding motif as X-X-Pro-X-Glu-X-X-(aromatic/acidic residue) (17).…”

mentioning

confidence: 99%

“…The structural analysis of the peptide-TRAF6 interaction has clarified the TRAF6-binding motif as X-X-Pro-X-Glu-X-X-(aromatic/acidic residue) (17). The TRAF6-binding motif is found not only in adaptor proteins such as IL-1R-associated kinase (17) and TIFA (18) but also in membranebound proteins such as CD40 and the receptor activator of NF-B RANK (17). Importantly, the TRAF6-binding motif is present in human and murine IL-25R.…”

mentioning

confidence: 99%

“…Among TRAF family proteins, TRAF6 exhibits the unique properties in that its TRAF-C domain interacts with a peptide motif distinct from that recognized by other TRAF proteins (17), supporting the findings that TRAF6 exhibits various functions in regulating adaptive and innate immunity, bone metabolism, and cell apoptosis (13)(14)(15)(16). The structural analysis of the peptide-TRAF6 interaction has clarified the TRAF6-binding motif as X-X-Pro-X-Glu-X-X-(aromatic/acidic residue) (17). The TRAF6-binding motif is found not only in adaptor proteins such as IL-1R-associated kinase (17) and TIFA (18) but also in membranebound proteins such as CD40 and the receptor activator of NF-B RANK (17).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling

Maezawa

Nakajima

Suzuki

et al. 2006

The Journal of Immunology

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IL-25 (IL-17E) induces IL-4, IL-5, and IL-13 production from an unidentified non-T/non-B cell population and subsequently induces Th2-type immune responses such as IgE production and eosinophilic airway inflammation. IL-25R is a single transmembrane protein with homology to IL-17R, but the IL-25R signaling pathways have not been fully understood. In this study, we investigated the signaling pathway under IL-25R, especially the possible involvement of TNFR-associated factor (TRAF)6 in this pathway. We found that IL-25R cross-linking induced NF-κB activation as well as ERK, JNK, and p38 activation. We also found that IL-25R-mediated NF-κB activation was inhibited by the expression of dominant negative TRAF6 but not of dominant negative TRAF2. Furthermore, IL-25R-mediated NF-κB activation, but not MAPK activation, was diminished in TRAF6-deficient murine embryonic fibroblast. In addition, coimmunoprecipitation assay revealed that TRAF6, but not TRAF2, associated with IL-25R even in the absence of ligand binding. Finally, we found that IL-25R-mediated gene expression of IL-6, TGF-β, G-CSF, and thymus and activation-regulated chemokine was diminished in TRAF6-deficient murine embryonic fibroblast. Taken together, these results indicate that TRAF6 plays a critical role in IL-25R-mediated NF-κB activation and gene expression.

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“…The recruitment of TRAF6 is necessary, as TRAF6-deficient mice have shown to be severely osteopetrotic, due to an impairment of osteoclastogenesis, preventing their resorptive activity (Kobayashi et al, 2003). However, while the TRAF6-dependent signaling cascade is used by other receptors like CD40 and TLR family members, it can only induce osteoclastogenesis via RANKL signaling (Ye et al, 2002).…”

Section: Differentiationmentioning

confidence: 99%