Abstract
RNA virus infections are detected by the RIG-I family of receptors, which induce type-I interferons through the mitochondrial protein MAVS. MAVS forms large prion-like polymers that activate the cytosolic kinases IKK and TBK1, which in turn activate NF-κB and IRF3, respectively, to induce interferons. Here we show that MAVS polymers recruit several TRAF proteins, including TRAF2, TRAF5, and TRAF6, through distinct TRAF-binding motifs. Mutations of these motifs that disrupted MAVS binding to TRAFs abrogated its ability to activate IRF3. IRF3 activation was also abolished in cells lacking TRAF2, 5, and 6. These TRAF proteins promoted ubiquitination reactions that recruited NEMO to the MAVS signaling complex, leading to the activation of IKK and TBK1. These results delineate the mechanism of MAVS signaling and reveal that TRAF2, 5, and 6, which are normally associated with NF-κB activation, also play a crucial role in IRF3 activation in antiviral immune responses. DOI:http://dx.doi.org/10.7554/eLife.00785.001.
Highlights
The innate immune system deploys germline-encoded pattern recognition receptors (PRRs) to detect pathogen invasion
As TRAF2 was recruited to NEMO in a manner that depended on MAVS, vesicular stomatitis virus (VSV), and UBD of NEMO, we investigated whether ubiquitination of TRAF2 plays a role in MAVS signaling
It is known that MAVS contains binding sites for several TRAF proteins (Seth et al, 2005; Xu et al, 2005), the role of these TRAF proteins in MAVS signaling has been enigmatic because cells lacking an individual TRAF protein, including TRAF2, TRAF3, TRAF5, and TRAF6, could still induce IFNβ normally in response to virus infection (Seth et al, 2005; Konno et al, 2009; Zeng et al, 2009)
Summary
The innate immune system deploys germline-encoded pattern recognition receptors (PRRs) to detect pathogen invasion. The receptors trigger the production of type-I interferons (e.g., IFNα and IFNβ) and other cytokines (e.g., TNFα and IL-6) to rapidly restrict the infection and further activate the adaptive immune system (Pichlmair and Reis e Sousa, 2007; Stetson and Medzhitov, 2006). RIG-I and MDA5, but not LGP2, harbor N-terminal tandem CARD domains that are crucial for triggering type-I IFN production. RIG-I contains a C-terminal regulatory domain that binds to RNA bearing 5′ triphosphate (Hornung et al, 2006; Pichlmair et al, 2006; Cui et al, 2008). Upon binding to different viral RNA ligands, RIG-I and MDA5 activate another CARD-containing protein, mitochondrial antiviral signaling protein (MAVS, known as IPS-1, VISA, and CARDIF), presumably through CARD–CARD interaction. MAVS in turn activates the transcription factors IRF3 and NF-κB, leading to interferon induction (Kawai et al, 2005; Meylan et al, 2005; Seth et al, 2005; Xu et al, 2005)
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