TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF

Takeshita, Fumihiko; Ishii, Ken J.; Kobiyama, Kouji; Kojima, Yoshitsugu; Coban, Cevayir; Sasaki, Shin; Ishii, Norihisa; Klinman, Dennis M.; Okuda, Kenji; Akira, Shizuo; Suzuki, Koichi

doi:10.1002/eji.200526151

Cited by 92 publications

(82 citation statements)

References 34 publications

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“…Immunoprecipitation and immunoblot analysis was performed as described in ref. 38 by using anti-FLAG M2 (Sigma), anti-HA (Covance, Berkeley, CA), anti-HA-Peroxidase (3F10) (Roche Diagnostics, Indianapolis, IN), anti-Atg5, anti-MAVS (IPS-1), or anti-phospho-IRF3 (Ser-396) antibody.…”

Section: Methodsmentioning

confidence: 99%

The Atg5–Atg12 conjugate associates with innate antiviral immune responses

Jounai

Takeshita

Kobiyama

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Autophagy is an essential process for physiological homeostasis, but its role in viral infection is only beginning to be elucidated. We show here that the Atg5-Atg12 conjugate, a key regulator of the autophagic process, plays an important role in innate antiviral immune responses. Atg5-deficient mouse embryonic fibroblasts (MEFs) were resistant to vesicular stomatitis virus replication, which was largely due to hyperproduction of type I interferons in response to immunostimulatory RNA (isRNA), such as virus-derived, double-stranded, or 5 -phosphorylated RNA. Similar hyperresponse to isRNA was also observed in Atg7-deficient MEFs, in which Atg5-Atg12 conjugation is impaired. Overexpression of Atg5 or Atg12 resulted in Atg5-Atg12 conjugate formation and suppression of isRNA-mediated signaling. Molecular interaction studies indicated that the Atg5-Atg12 conjugate negatively regulates the type I IFN production pathway by direct association with the retinoic acid-inducible gene I (RIG-I) and IFN-␤ promoter stimulator 1 (IPS-1) through the caspase recruitment domains (CARDs). Thus, in contrast to its role in promoting the bactericidal process, a component of the autophagic machinery appears to block innate antiviral immune responses, thereby contributing to RNA virus replication in host cells.innate immunity ͉ signal transduction ͉ type I interferon

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Section: Methodsmentioning

confidence: 99%

The Atg5–Atg12 conjugate associates with innate antiviral immune responses

Jounai

Takeshita

Kobiyama

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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520

499

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“…TRAF3 and TICAM1 form the complex to induce IFN-β via TRAF2/6. Con- versely, TRAF1, TRAF4 and SARM act as inhibitors in TICAM1-dependent signaling [33][34][35][36]. As amphioxus TRAF2, TRAF3, TRAF4, TRAF6, and SARM were cloned by our group in other studies [37][38][39], we investigated the relationship between these molecules and bbt-TICAM.…”

Section: Bbtticam Failed To Interact With Bbttraf3 4 and 6 But Assmentioning

confidence: 99%

“…The RHIM motif within the C terminus interacts with RIP1/3 for the induction of mitochondria-independent apoptosis via formation of an RIP/FADD/caspase-8 complex [26,30,31]. Conversely, TICAM1-mediated signaling can be negatively regulated by direct interaction with TRAF1 and TRAF4 via its N-terminal domain and through interaction of SARM via its TIR domain [33][34][35]. Zebrafish TICAM1, co-localized with Golgi apparatus [18], stimulates NF-κB activation via RIP and TBK1, but not with TRAF6, due to the lack of TRAF6-binding motifs in zebrafish TICAM1 [17].…”

Section: The Regulatory Mechanism Of Bbtticam On Nf-κb Activation Shementioning

confidence: 99%

Characterization of bbtTICAM from amphioxus suggests the emergence of a MyD88-independent pathway in basal chordates

et al. 2011

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The MyD88-independent pathway, one of the two crucial TLR signaling routes, is thought to be a vertebrate innovation. However, a novel Toll/interleukin-1 receptor (TIR) adaptor, designated bbtTICAM, which was identified in the basal chordate amphioxus, links this pathway to invertebrates. The protein architecture of bbtTICAM is similar to that of vertebrate TICAM1 (TIR-containing adaptor molecule-1, also known as TRIF), while phylogenetic analysis based on the TIR domain indicated that bbtTICAM is the oldest ortholog of vertebrate TICAM1 and TICAM2 (TIR-containing adaptor molecule-2, also known as TRAM). Similar to human TICAM1, bbtTICAM activates NF-κB in a MyD88-independent manner by interacting with receptor interacting protein (RIP) via its RHIM motif. Such activation requires bbtTICAM to form homodimers in endosomes, and it may be negatively regulated by amphioxus SARM (sterile α and armadillo motif-containing protein) and TRAF2. However, bbtTICAM did not induce the production of type I interferon. Thus, our study not only presents the ancestral features of vertebrate TICAM1 and TI-CAM2, but also reveals the evolutionary origin of the MyD88-independent pathway from basal chordates, which will aid in understanding the development of the vertebrate TLR network.

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“…GM-DCs or FL-DCs were treated with or without 1, 3, or 10 g/ml NЈ-CARD-PTD or 1 M of CpG ODN for 24 h and the supernatants were subjected to ELISA for mouse IFN-␣, IFN-␤ (PBL Biomedical Laboratories), or IL-12 p40 (Invitrogen). RAW264.7 cells were treated with 1 g/ml LPS or 10 g/ml NЈ-CARD-PTD for 3,6,12,18,24, and 48 h. The levels of mRNA for TNF-␣, IL-6, IFN-␣, IFN-␤, IP-10, and ␤-actin were examined by RT-PCR as described previously (5,22).…”

Section: Elisa and Rt-pcrmentioning

confidence: 99%