Negative regulation of NF-κB activity by brain-specific TRIpartite Motif protein 9

Shi, Mude; Cho, Hyelim; Inn, Kyung‐Soo; Yang, Aerin; Zhao, Zhen; Liang, Qiming; Versteeg, Gijs A.; Amini-Bavil-Olyaee, Samad; Wong, Li Chin; Zloković, Berislav V.; Park, Hee-Sung; Garcı́a-Sastre, Adolfo; Jung, Jae U.

doi:10.1038/ncomms5820

Cited by 70 publications

(62 citation statements)

References 57 publications

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“…Extending these studies, a recent report identified TRIM5 as a regulator of autophagy that acts as a restriction factor against HIV-1 (Mandell et al, 2014). TRIM family members largely function in negative regulatory circuits, as was recently demonstrated for TRIM9, a negative regulator of NF-κB pro-inflammatory cytokine signaling (Shi et al, 2014). An increasing number of TRIM proteins have also been described as enhancers of innate immune pathways, as in the case of TRIM44 stabilizing MAVS to enhance signaling (Yang et al, 2013).…”

Section: Discussionmentioning

confidence: 80%

Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation

et al. 2015

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Summary CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 mutations. Here we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigate CARD9 regulation. We showed that the C-terminal truncated CARD9 protective variant acted in a dominant negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that Trim62-deficient mice have increased susceptibility to fungal infection, similar to Card9-deficient mice. This study utilizes a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.

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Section: Discussionmentioning

confidence: 80%

Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation

et al. 2015

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“…The purification of mouse cGAS protein including the unnatural amino acid was described previously (Shi et al, 2014). Briefly, the Ser291 (AGC) codon was replaced by the pSer291 (UAG) amber codon by site-directed mutagenesis (Stratagene).…”

Section: Methodsmentioning

confidence: 99%

Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway

et al. 2015

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SUMMARY Upon DNA stimulation, cyclic GMP-AMP synthetase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts’ immune responses to DNA stimulation.

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“…TRIM9 is highly expressed in the central nervous system [26,27]. Recently, TRIM9l was reported to negatively regulate NF-κB signaling by preventing β-TrCP binding to its substrate IκB [28]. However, the role of TRIM9 in virus-induced type I IFN signaling and inflammation is still not clear.…”

Section: Introductionmentioning

confidence: 94%

“…It has been reported that the phosphorylation of TRIM9 at its RING domain (Ser76 and Ser80) is critical for its inhibitory effect on NF-κB signaling [28]. We examined whether TRIM9s-mediated type I IFN activation is also dependent on TRIM9s phosphorylation.…”

Section: Trim9 Promotes Tbk1-mediated Signaling Through Its E3 Ligasementioning

confidence: 99%

“…Recently, TRIM9l has been reported to be a negative regulator of NF-κB-dependent pro-inflammatory signaling through inhibition of β-TrCP activity [28]. To investigate how TRIM9 regulates IRF3 and NF-κB signaling in antiviral immunity, we examined the functions of TRIM9s and TRIM9l in RIG-I-and cGAS-triggered NF-κB or IRF3 activation.…”

Section: Trim9s Balances Irf3 and Nf-κb Signaling Upon Viral Infectionmentioning

confidence: 99%

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TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1

et al. 2016

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Type I interferon (IFN) is an important component of antiviral innate immune signaling mediated by viral DNAand RNA recognition by the DNA sensor cGAS and RNA sensors RIG-I and MDA5. Activation of these DNA and RNA sensors leads to the recruitment of STING and MAVS, respectively, and converges on TANK-binding kinase 1 (TBK1) signaling for subsequent phosphorylation of IFN regulatory factor 3 (IRF3). However, the mechanisms that control TBK1 activation are still poorly defined. Here, we identify tripartite motif 9 short isoform (TRIM9s) as a positive regulator in type I IFN signaling. Upon viral infection, TRIM9s undergoes Lys-63-linked auto-polyubiquitination and serves as a platform to bridge GSK3β to TBK1, leading to the activation of IRF3 signaling. Interestingly, we found that TRIM9s selectively inhibits the production of pro-inflammatory cytokines, but enhances the expression of type I IFNs as well as IFN-stimulated genes, in response to viral infection. Our findings reveal novel dual functions of TRIM9s in antiviral immunity, which serve to balance pro-inflammatory response and production of type I IFNs.

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Negative regulation of NF-κB activity by brain-specific TRIpartite Motif protein 9

Cited by 70 publications

References 57 publications

Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation

Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation

Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway

TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1

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