A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation

Zhao, Hang; Li, Connie C.; Pardo, Jorge; Chu, Peter C.; Liao, Charlene; Huang, Jianing; Dong, John G.; Zhou, Xiulan; Huang, Qi; Huang, Betty; Bennett, Mark K.; Molineaux, Susan M.; Lu, Henry; Daniel-Issakani, Sarkiz; Payan, Donald G.; Masuda, Esteban S.

doi:10.4049/jimmunol.174.9.5288

Cited by 53 publications

(56 citation statements)

References 54 publications

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“…Recent studies indicate that several ubiquitin E3 ligases are involved in the regulation of innate immune signaling (16)(17)(18)(19)(20)(21). We previously reported that the E3 ubiquitin ligase RNF125 negatively regulates RIG-I signaling (17), and it has been reported that RNF125 is also a T-cell activator (23), which suggests the presence of plural functions of RNF125 in regulation of cell proliferation. To identify genes affected by RNF125, we conducted microarray analysis (mock-vs. RNF125-transfected 293T cells) and found the gene for TRIM23 up-regulated ∼3-fold (Fig.…”

Section: Resultsmentioning

confidence: 99%

Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense

Arimoto

Funami

Saeki

et al. 2010

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

148

124

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The rapid induction of type I IFN is a central event of the innate defense against viral infections and is tightly regulated by a number of cellular molecules. Viral components induce strong type I IFN responses through the activation of toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as an RNA helicase RIG-I and/ or MDA5. According to recent studies, the NF-κB essential modulator (NEMO, also called IKKγ) is crucial for this virus-induced antiviral response. However, the precise roles of signal activation by NEMO adaptor have not been elucidated. Here, we show that virus-induced IRF3 and NF-κB activation depends on the K(lys)-27-linked polyubiquitination to NEMO by the novel ubiquitin E3 ligase triparite motif protein 23 (TRIM23). Virus-induced IRF3 and NF-κB activation, as well as K27-linked NEMO polyubiquitination, were abrogated in TRIM23 knockdown cells, whereas TRIM23 knockdown had no effect on TNFα-mediated NF-κB activation. Furthermore, in NEMO-deficient mouse embryo fibroblast cells, IFN-stimulated response element-driven reporter activity was restored by ectopic expression of WT NEMO, as expected, but only partial recovery by NEMO K165/309/325/326/344R multipoints mutant on which TRIM23-mediated ubiquitin conjugation was substantially reduced. Thus, we conclude that TRIM23-mediated ubiquitin conjugation to NEMO is essential for TLR3-and RIG-I/MDA5-mediated antiviral innate and inflammatory responses.innate immunity | signal transduction | virus infection U pon viral infection, host cells recognize the viral components and activate innate immune signaling to exert antiviral responses (1-4). RIG-I and/or MDA5 sense viral dsRNA (5-8) and are recruited to another antiviral signaling adaptor, IPS-1 (also called MAVS, Cardif, or VISA) (9-12). IPS-1 directly interacts with TRAF3 and triggers auto-ubiquitination of TRAF3, which then activates TBK1 and IKKε, leading to activation of transcription factors NF-κB and IRF3 (13,14). A recent study indicated that NEMO acts upstream of TBK1 and IKKε and is essential for virus-induced TLR3-and RIG-I/MDA5-mediated antiviral activation (15).Because rapid induction of type I IFN expression is the key process in initiating the innate antiviral response, clarification of NEMO-mediated antiviral signaling is important for understanding innate immune signaling; however, NEMO-mediated antiviral signaling is not well elucidated. Recent studies indicate that several ubiquitin E3 ligases are involved in the regulation of innate immune signaling (16-21). We identified the ubiquitin E3 ligase TRIM23 (Triparite motif protein 23), also named ADP ribosylation factor domain protein 1 (ARD1), which was reported to have E3 ligase activity in vitro (22), that functioned as an E3 ligase for NEMO ubiquitin conjugation. TRIM23 exerts a potent antiviral state following its overexpression. Furthermore, we demonstrated that antiviral activity depends not on K(Lys)63-linked but on K27-linked polyubiquitin conjugation to multiple sites of NEMO by TRIM23 expression. Virus-in...

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Section: Resultsmentioning

confidence: 99%

Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense

Arimoto

Funami

Saeki

et al. 2010

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

148

124

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“…Using a yeast-two hybrid screening, we isolated RNF125 as an interacting protein with UbcH8. RNF125, a RING motif containing proteins, can act as a ubiquitin E3 ligase (25). A schematic diagram of RNF125 and its mutants used in this paper are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…RNF125 interacts with several E2 enzymes (25), and one of these enzymes most likely acts as an E2 for ubiquitin conjugation to RIG-I. To identify the E2 acting upstream of RNF125 in RIG-I conjugation, we performed an in vitro assay examining ubiquitin conjugation to RIG-I [see supporting information (SI) Fig.…”

Section: E2 Enzymes Involved In Ubiquitinmentioning

confidence: 99%

“…The result of the search was the identification of RNF125 (Homo sapiens ring-finger protein 125, GenBank accession no. NM017831), also named TRAC-1 (T cell RING protein identified in activation screen), an E3 ubiquitin ligase serving a positive regulatory role in T cell activation (25), that functioned as an E3 ligase for RIG-I ubiquitin conjugation. Ubiquitinconjugated RIG-I was degraded in a proteasome-dependent manner.…”

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confidence: 99%

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Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125

Arimoto

Takahashi

Hishiki

et al. 2007

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

405

408

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Retinoic acid-inducible gene I (RIG-I) plays a pivotal role in the regulation of cytokine production induced by pathogens. The RIG-I also augments the production of IFN and other cytokines via an amplification circuit. Because the production of cytokines is closely controlled, up-and down-regulation of RIG-I signaling also needs strict regulation. The mechanism of this regulation, however, remains elusive. Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.innate immunity ͉ signal transduction

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“…Much of the work on TCR signalling and T-cell activation has been focused on positive regulators [10][11][12][13] ; however, more attention has been paid to negative regulators of T-cell activation from the cell surface to the nucleus in recent years 14 . For example, CD45 and SH2 domaincontaining phosphatase-1 dephosphorylate lymphocyte-specific protein tyrosine kinase, resulting in the cessation of TCR signal 5,6 .…”

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confidence: 99%