TRADD protein is an essential component of the RIG-like helicase antiviral pathway.
Upon detection of viral RNA, the helicases RIG-I and/or MDA5 trigger, via their adaptor Cardif (also known as IPS-1, MAVS, or VISA), the activation of the transcription factors NF-kappaB and IRF3, which collaborate to induce an antiviral type I interferon (IFN) response. FADD and RIP1, known as mediators of death-receptor signaling, are implicated in this antiviral pathway; however, the link between death-receptor and antiviral signaling is not known. Here we showed that TRADD, a crucial adaptor of tumor necrosis factor receptor (TNFRI), was important in RIG-like helicase (RLH)-mediated signal transduction. TRADD is recruited to Cardif and orchestrated complex formation with the E3 ubiquitin ligase TRAF3 and TANK and with FADD and RIP1, leading to the activation of IRF3 and NF-kappaB. Loss of TRADD prevented Cardif-dependent activation of IFN-beta, reduced the production of IFN-beta in response to RNA viruses, and enhanced vesicular stomatitis virus replication. Thus, TRADD is not only an essential component of proinflammatory TNFRI signaling, but is also required for RLH-Cardif-dependent antiviral immune responses.
Michallet
Marie-Cécile
MC
Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Meylan
Etienne
E
Ermolaeva
Maria A
MA
Vazquez
Jessica
J
Rebsamen
Manuele
M
Curran
Joseph
J
Poeck
Hendrik
H
Bscheider
Michael
M
Hartmann
Gunther
G
König
Martin
M
Kalinke
Ulrich
U
Pasparakis
Manolis
M
Tschopp
Jürg
J
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D004265:DNA Helicases / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism*; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface; D018353:Rhabdoviridae Infections / Q000276:immunology* / Q000821:virology; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism*; D048008:TNF Receptor-Associated Factor 3 / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D018116:Vesiculovirus / Q000276:immunology* / Q000502:physiology; D000097905:Roundabout Proteins
D048868:Adaptor Proteins, Signal Transducing; D004265:DNA Helicases; D053200:Fas-Associated Death Domain Protein; D020690:GTPase-Activating Proteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D053199:TNF Receptor-Associated Death Domain Protein; D048008:TNF Receptor-Associated Factor 3; D044767:Ubiquitin-Protein Ligases; C505534:Fadd protein, mouse; C494232:IRF3 protein, human; C490620:Ralbp1 protein, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C100814:Tank protein, mouse