Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif

Abstract

Upon recognition of viral infection, RIG-I and Helicard recruit a newly identified adapter termed Cardif, which induces type I interferon (IFN)-mediated antiviral responses through an unknown mechanism. Here, we demonstrate that TRAF3, like Cardif, is required for type I interferon production in response to intracellular doublestranded RNA. Cardif-mediated IFNa induction occurs through a direct interaction between the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) within Cardif. Interestingly, while the entire N-terminus of TRAF3 was functionally interchangeable with that of TRAF5, the TRAF domain of TRAF3 was not. Our data suggest that this distinction is due to an inability of the TRAF domain of TRAF5 to bind the TIM of Cardif. Finally, we show that preventing association of TRAF3 with this TIM by mutating two critical amino acids in the TRAF domain also abolishes TRAF3-dependent IFN production following viral infection. Thus, our findings suggest that the direct and specific interaction between the TRAF domain of TRAF3 and the TIM of Cardif is required for optimal Cardif-mediated antiviral responses.

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

“…In the nucleus, NF-kB and IRF3, as well as other transcription factors and coactivators, collaborate to facilitate the transcription of type I IFN genes. [15][16][17] Complicated virus-host interactions occur during the course of a viral infection. The host cells utilize PRRs to recognize viral components that trigger the induction of type I IFNs and other antiviral genes.…”

A functional C-terminal TRAF3-binding site in MAVS participates in positive and negative regulation of the IFN antiviral response

“…Functionally, the CARD and TM domains appear to be critical for MAVS dimerization and for relaying the signal from RIG-I to downstream adapter molecules [12,[14][15][16][17]. The Pro region harbors two distinct TIMs, one located at aa 143-PVQET-147 that binds TRAF2 and TRAF3, and a second TIM located at aa 153-PGENSE-158 that exclusively binds TRAF6 [13,18]. An alternate TRAF6-binding site is located in the C-terminus of MAVS at aa 455-PEENEY-460 [13], and both N-and C-terminal sites are required for TRAF6-mediated activation of the NF-κB pathway [13].…”

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

“…We also investigated the effects of TRAF5, which is structurally homologous to TRAF3 [9], on IFN-β expression. As shown in Figure 2 …”

“…Upon viral recognition by RLRs, dimerization of MAVS recruits TNF receptor-associated factors (TRAFs), leading to the activation of transcription factors such as nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF)-3/7. Subsequently, homodimerized IRFs and activated NF-κB translocate from the cytoplasm to the nucleus, resulting in enhanced transcription of pro-inflammatory cytokines and type I interferons (IFNs) [7][8][9][10][11].…”

“…In RLR signaling, TRAF2, TRAF3, TRAF5, and TRAF6 have been shown to be associated with MAVS. TRAF3 is essential for IRF3 activation [9]. TRAF2 and TRAF5 have been shown to be required for the activation of IRF3 and NF-κB [8,10].…”