TRIM21 Promotes Innate Immune Response to RNA Viral Infection through Lys27-Linked Polyubiquitination of MAVS

Abstract

Human innate immunity responds to viral infection by activating the production of interferons (IFNs) and proinflammatory cytokines. The mitochondrial adaptor molecule MAVS plays a critical role in innate immune response to viral infection. In this study, we show that TRIM21 (tripartite motif-containing protein 21) interacts with MAVS to positively regulate innate immunity. Under viral infection, TRIM21 is upregulated through the IFN/JAK/STAT signaling pathway. Knockdown of TRIM21 dramatically impairs innate immune response to viral infection. Moreover, TRIM21 interacts with MAVS and catalyzes its K27-linked polyubiquitination, thereby promoting the recruitment of TBK1 to MAVS. Specifically, the PRY-SPRY domain of TRIM21 is the key domain for its interaction with MAVS, while the RING domain of TRIM21 facilitates the polyubiquitination chains of MAVS. In addition, the MAVS-mediated innate immune response is enhanced by both the PRY-SPRY and RING domains of TRIM21. Mutation analyses of all the lysine residues of MAVS further revealed that Lys325 of MAVS is catalyzed by TRIM21 for the K27-linked polyubiquitination. Overall, this study reveals a novel mechanism by which TRIM21 promotes the K27-linked polyubiquitination of MAVS to positively regulate innate immune response, thereby inhibiting viral infection. IMPORTANCE Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. MAVS plays a critical role in innate immune response to RNA viral infection. In this study, we demonstrated that TRIM21 targets MAVS to positively regulate innate immunity. Notably, TRIM21 targets and catalyzes K27-linked polyubiquitination of MAVS and then promotes the recruitment of TBK1 to MAVS, leading to upregulation of innate immunity. Our study outlines a novel mechanism by which the IFN signaling pathway blocks RNA virus to escape immune elimination.

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

“…TBK1 mutations observed in ALS and FTLD-TDP patients were previously shown to reduce the activation of IRF3 [29,38,84,19], and our observation of LOF variants in IRF3, IRF7 and IRF8 in FTLD-TDP patients thus points to alternative genetic insults that may have similar consequences. TRIM21, with LOF variants in 3 FTLD-TDP patients, also positively regulates innate immunity by facilitating the recruitment of TBK1 to MAVS through the regulation of MAVS polyubiquitination [98]. DHX58 (mutated in 4 FTLD-TDP patients) was originally thought to be a negative regulator of the RIG-I-like receptor family [77,39,100,76]; however, more recent work has shown the importance of DHX58 in the enhancement of MDA5-mediated antiviral signaling in vivo [78,92].…”

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

“…Aside from the prototypical K63 and K48 ubiquitin linkages, other chain types can also be critical in certain situations. For example, in addition to its role in autophagy, K27-linked polyubiquitin mediates the recruitment of MAVS to TBK1, leading to IRF3 activation and IFN-I production in response to viral infection [95,96]. Upon infection with several viruses including HCV, Newcastle disease virus (NDV), SeV, VSV and Coxsackie virus B3 (CVB3), TRIM21 is expressed and interacts with MAVS through its PRY-SPRY domain.…”

“…Upon infection with several viruses including HCV, Newcastle disease virus (NDV), SeV, VSV and Coxsackie virus B3 (CVB3), TRIM21 is expressed and interacts with MAVS through its PRY-SPRY domain. This association allows for the conjugation of K27-linked polyubiquitin onto the K325 residue of MAVS for downstream signalling [95,96].…”

Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways

“…Non-degradative ubiquitination also favors the interaction of MAVS with downstream effectors. For example, viral infection induces the expression of the E3 ligase TRIM21, which binds MAVS to promote its K27-linked polyubiquitination at lysine 325 and its association with TBK1 (Xue et al, 2018). Moreover, TRIM proteins regulate the recruitment of IKKγ/NEMO to MAVS signalosome through their own ubiquitination.…”