The E3-Ligase TRIM Family of Proteins Regulates Signaling Pathways Triggered by Innate Immune Pattern-Recognition Receptors

Versteeg, Gijs A.; Rajsbaum, Ricardo; Sánchez-Aparicio, María Teresa; Maestre, Ana; Valdiviezo, Julio; Shi, Mude; Inn, Kyung Soo; Fernández-Sesma, Ana; Jung, Jae U.; García‐Sastre, Adolfo

doi:10.1016/j.immuni.2012.11.013

Cited by 275 publications

(319 citation statements)

References 32 publications

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“…Recently, a systematic analysis of all 75 known human TRIMs revealed that nearly half of these TRIMs could enhance the innate immune response. Moreover, mutational analysis demonstrated that all of the six tested TRIMs required an intact RING domain for their activity (30), suggesting that the RING domain may serve as a prevailing machinery for TRIMs. Intriguingly, TRIM14 does not contain an N-terminal RING domain but still potently enhances the innate immune response.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou

Jia

Xue

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

116

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Innate immunity provides the first line of host defense against invading microbial pathogens. This defense involves retinoic acidinducible 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 acidinducible gene-I-like receptors.A ctivation of the innate immune response involves the detection of pathogen-associated molecular patterns (PAMPs), such as microbial nucleic acids, proteins, lipids, and carbohydrates. PAMPs are recognized by cellular pattern recognition receptors (PRRs), including Toll-like receptors, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors, and C-type lectin receptors. Upon recognition, PRRs trigger a series of signaling events that lead to the induction of type I IFNs and proinflammatory cytokines (1).RLRs such as RIG-I and melanoma differentiation-associated antigen 5 (MDA5) recognize cytosolic viral RNA (2). Upon binding of RNA to the helicase domain, RIG-I or MDA5 undergoes a conformational change (3) and is recruited to the mitochondrial antiviral signaling (MAVS) adaptor. After binding of RIG-1 or MAD5, MAVS recruits various downstream molecules and further activates two kinase complexes: the noncanonical IκB kinases (IKKs) [TANK-binding kinase 1 (TBK1)/IKKi] and the canonical IKK complexes comprised of IKKα, IKK-β, and NF-κB essential modulator (NEMO) (4, 5). The TBK1/IKKi kinases phosphorylate IFN regulatory factor 3/7 (IRF3/7), which translocates to the nucleus and drives the transcription of IFNs (6). The canonical IKKs phosphorylate IκBα, resulting in the ubiquitination and proteasomal degradation of IκBα. NF-κB then is released to the nucleus and stimulates the expression of proinflammatory genes (7).MAVS-deficient mice show abolished virus-triggered induction of IFNs and increased susceptibility to viral infection (8), indicating that MAVS is essential for the innate immune response. MAVS consists of an N-terminal caspase activation and recruitment domain, a proline-rich domain, and a C-terminal transmembrane domain that targets it to the mitochondrial outer membrane (9). It has been suggested that the mitochondrial outer membrane pr...

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Section: Discussionmentioning

confidence: 99%

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

Zhou

Jia

Xue

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

116

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“…Ubiquitination is one of the most versatile PTMs and is important for antiviral responses. Many members of the TRIM family can induce K63-or K48-linked ubiquitination [32]. For example, TRIM25 and TRIM56 can induce RIG-I and STING ubiquitination, respectively, by K63-mediated linkage, which are essential for type I IFN production [33,34].…”

Section: Discussionmentioning

confidence: 99%

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

et al. 2015

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Type I interferon (IFN) production plays pivotal roles in host antiviral innate immune responses, but an excessive production of type I IFN leads to the development of immunopathological conditions. Investigations on the regulatory mechanisms underlying host type I IFN production are currently of great interest. Here, we found that the expression of lectin family member Siglec1 was upregulated by viral infection in macrophages, which was dependent on the IFN/JAK/STAT1 signaling pathway. Siglec1 was found to negatively regulate viral infection-triggered type I IFN production. Mechanistically, Siglec1 associates with DAP12 to recruit and activate the scaffolding function of SHP2; SHP2 then recruits E3 ubiquitin ligase TRIM27, which induces TBK1 degradation via K48-linked ubiquitination at Lys251 and Lys372. Therefore, viral infection-induced upregulation of Siglec1 feedback loop inhibits type I IFN production and suppresses antiviral innate immune responses. Our study outlines a novel mechanism of negative regulation of type I IFN production, which may help virus to escape immune elimination.

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“…In particular, the T. adhaerens TRIM has multiple human co-orthologs within paralogons of the MHC, neurotrophin or JN sets, and all of them share the same domain structure (72). Among them are TRIM1 and TRIM9, two key modulators of the IFN pathway that strongly inhibit viral growth (73). In the absence of IFN, an antiviral activity of the T. adhaerens TRIM might proceed via direct binding (and ubiquitination) of viral proteins as for TRIM5 in primates, or via modulation of expression of other antiviral factors.…”

Section: Discussionmentioning

confidence: 99%

The Proto-MHC of Placozoans, a Region Specialized in Cellular Stress and Ubiquitination/Proteasome Pathways

Suurväli

Jouneau

Thépot

et al. 2014

The Journal of Immunology

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The E3-Ligase TRIM Family of Proteins Regulates Signaling Pathways Triggered by Innate Immune Pattern-Recognition Receptors

Cited by 275 publications

References 32 publications

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

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

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

The Proto-MHC of Placozoans, a Region Specialized in Cellular Stress and Ubiquitination/Proteasome Pathways

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