TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I–like receptor-mediated innate immune response

Significance The innate immune system plays a key role in host defense that involves the detection of microbial components and a series of signaling events that lead to production of interferons and cytokines. Recently, the identification of mitochondrial antiviral-signaling (MAVS) protein placed mitochondria at the forefront of the innate immune response against virus infection. However, how the MAVS signaling complex is assembled and regulated on the mitochondria outer membrane is only partially understood. Here we show that tripartite motif 14 (TRIM14) facilitates the assembly of the MAVS complex assembly. Upon virus infection, TRIM14 recruits NF-κB essential modulator (NEMO) to the MAVS complex via ubiquitin chains. Knockdown of TRIM14 disrupts the MAVS–NEMO association and attenuates the antiviral response. Our results thus provide a missing link in MAVS-mediated innate immune signaling. Innate immunity provides the first line of host defense against invading microbial pathogens. This defense involves retinoic acid-inducible gene-I–like receptors that detect viral RNA and activate the mitochondrial antiviral-signaling (MAVS) protein, an adaptor protein, leading to activation of the innate antiviral immune response. The mechanisms by which the MAVS signalosome assembles on mitochondria are only partially understood. Here, we identify tripartite motif 14 (TRIM14) as a mediator in the immune response against viral infection. TRIM14 localizes to the outer membrane of mitochondria and interacts with MAVS. Upon viral infection, TRIM14 undergoes Lys-63–linked polyubiquitination at Lys-365 and recruits NF-κB essential modulator to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3 and NF-κB pathways. Knockdown of TRIM14 disrupts the association between NF-κB essential modulator and MAVS and attenuates the antiviral response. Our results indicate that TRIM14 is a component of the mitochondrial antiviral immunity that facilitates the immune response mediated by retinoic acid-inducible gene-I–like receptors.

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