Cutting Edge: Autoantigen Ro52 Is an Interferon Inducible E3 Ligase That Ubiquitinates IRF-8 and Enhances Cytokine Expression in Macrophages

Kong, Hee Jeong; Anderson, David E.; Lee, Chang Hoon; Jang, Moon Kyoo; Tamura, Tomohide; Tailor, Prafullakumar; Cho, Hyun Kook; Cheong, JaeHun; Xiong, Huabao; Morse, Herbert C.; Ozato, Keiko

doi:10.4049/jimmunol.179.1.26

Cited by 177 publications

(184 citation statements)

References 26 publications

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“…Deletion of the SPRY domain in TRIM11, TRIM21, and TRIM25 abrogated the interaction of the proteins with their binding partner proteins. 26,32,33 In this study we found that the SPRY domain was essential for the nuclear localization of TRIM22, and TRIM22 lacking the SPRY domain was localized exclusively to the cytoplasm of HepG2 cells and lost its suppressive activity on HBV CP. As no nuclear localization signal (NLS) is found in the SPRY domain of TRIM22 and the SPRY domain has often been implicated in protein-protein interactions, we suspect that TRIM22 may be transported into the nucleus by binding to other nuclear proteins through its SPRY domain.…”

Section: Discussionmentioning

confidence: 82%

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Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain

et al. 2009

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Members of the tripartite motif (TRIM) family are a part of the innate immune system to counter intracellular pathogens. TRIM22 has been reported to possess antiretroviral activity. Here we report that TRIM22 is involved in antiviral immunity against hepatitis B virus (HBV). Our results showed that TRIM22, being a strongly induced gene by interferons in human hepatoma HepG2 cells, could inhibit HBV gene expression and replication in a cell culture system as well as in a mouse model system. Importantly, it was found that TRIM22 could inhibit the activity of HBV core promoter (CP) in a dose-dependent manner. However, TRIM22 lacking the C terminal SPRY domain lost this activity. Further study showed that the SPRY domain deletion mutant was localized exclusively to the cytoplasm of HepG2 cells. In contrast, the wild-type TRIM22 was localized to the nucleus, as expected for a transcriptional suppressor. Interestingly, although RING domain mutants of TRIM22 were localized to the nucleus, they could not inhibit HBV CP activity, indicating that TRIM22-mediated anti-HBV activity was dependent on the nuclear-located RING domain. W ith over 300 million carriers, hepatitis B virus (HBV) infection remains a major public health problem worldwide. 1 Classified in the Hepadnaviridae family, HBV is a small, enveloped DNA virus with a genome size of 3.2 kb. HBV replicates its partially double-stranded DNA genome within core particles by reverse transcription of encapsulated 3.5-kb pregenomic RNA (pgRNA), and thus is related to retroviruses. 2 The core promoter (CP) is responsible for the synthesis of pgRNA, and therefore the regulation of this promoter is important in the viral life cycle. It is well established that resolution of HBV infection is critically dependent on adaptive immunity, especially on HBVspecific cytotoxic T lymphocytes response. However, many studies also indicate that an innate immune response is crucial for early clearance of HBV infection. 3 For example, activation of Toll-like receptor signaling can inhibit HBV replication in vivo, and overexpression of an innate antiviral molecule, APOBEC3G, has also been shown to interfere with HBV replication efficiently. 4,5 Recent studies show that many members of the tripartite motif (TRIM) superfamily are expressed in response to interferons (IFNs) and display antiviral properties, targeting retroviruses in particular. 6,7 TRIM5␣, TRIM19, TRIM22, and TRIM28 were all demonstrated to play important roles in antiretroviral activities. [8][9][10][11][12] It has been speculated that the TRIM proteins may represent a new and widespread class of antiviral molecules involved in innate immunity. 6,7 The TRIM family is characterized by a combination of RING, B-Box, and coiled-coil domains, followed by one of several C-terminal domains. 13 To date, nearly 70 TRIM family members have been identified, yet the most intensively studied TRIM protein may be

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Section: Discussionmentioning

confidence: 82%

“…1A). 11,[26][27][28] To further investigate whether TRIM22 was induced in an IFN-dependent manner, we examined the expression level of TRIM22 protein by western blot using anti-TRIM22 antibody in HepG2 cells stimulated with IFN-␣ or IFN-␥. As shown in Fig.…”

Section: Expression Of Trim Family Molecules In Ifn-mentioning

confidence: 99%

Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain

et al. 2009

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“…Both TRIM27 and TRIM21 have been shown to interact with the IKKs repressing their activity and as a result pro-inflammatory cytokine production [27,88]. TRIM21 also interacts with the IRFs 3, 7,8, each interaction resulting in repression of NFKB and IFN promoter activity [85,[109][110][111]. On the contrary, some TRIMs function as positive regulators of these pathways.…”

Section: Figure Legendsmentioning

confidence: 99%

“…Additional targets for Ro52/TRIM21 have been reported -IRF8 for example is positively regulated by Ro52/TRIM21 ubiquitination, resulting in modest increases in IL8-dependent cytokine production [85]. In a separate study Ro52/TRIM21 has been demonstrated to stabilise IRF3 levels and therefore positively regulates IRF3 activity during antiviral responses [86].…”

Section: Regulation Of Transcriptional Responsesmentioning

confidence: 99%

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

2011

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“…TRIM21 has been reported to ubiquitinate IRF3, IRF5, IRF7, and IRF8 (9,(15)(16)(17)(18), thus affecting the expression of IRF target genes such as IFNb, IL-6, and IL-12/IL-23 p40. Two independent studies demonstrate that Trim21 2/2 cells overexpress proinflammatory cytokines after TLR activation in vitro (8,9).…”

mentioning

confidence: 99%

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Sjöstrand

Ambrosi

Brauner

et al. 2013

The Journal of Immunology

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Tripartite-motif 21 (TRIM21) is an E3 ubiquitin ligase that regulates innate immune responses by ubiquitinating IFN regulatory factors (IRFs). TRIM21 is mainly found in hematopoietic cells in which its expression is induced by IFNs during viral. infections and in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren’s syndrome. However, the exact molecular mechanism by which the expression of the Trim21 gene is regulated is unknown. In this study, we demonstrate that IFNs induce Trim21 expression in immune cells via IRFs and that IFN-α and IFN-β are the most potent inducers of Trim21. A functional IFN-stimulated response element but no conserved IFN-γ–activated site was detected in the promoter of Trim21. IRF1 and IRF2 strongly induced Trim21 expression in an IFN-stimulated response element–dependent manner, whereas IRF4 and IRF8 strongly repressed the IRF1-mediated induction of Trim21. Consistent with this observation, baseline expression of Trim21 was elevated in Irf4−/− cells. TRIM21, IRF1, and IRF2 expression was increased in PBMCs from patients with Sjögren’s syndrome compared with healthy controls. In contrast, IRF4 and IRF8 expression was not increased in PBMCs from patients. The IFN-γ–mediated induction of Trim21 was completely abolished by inhibiting protein synthesis with cycloheximide, and Trim21 expression could not be induced by IFN-γ in Irf1−/− cells, demonstrating that IFN-γ induces Trim21 indirectly via IRF1 and not directly via STAT1 activation. Our data demonstrate that multiple IRFs tightly regulate expression of Trim21 in immune cells, suggesting that a well-controlled expression of the E3 ligase TRIM21 is important for regulation of immune responses.

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Cutting Edge: Autoantigen Ro52 Is an Interferon Inducible E3 Ligase That Ubiquitinates IRF-8 and Enhances Cytokine Expression in Macrophages

Cited by 177 publications

References 26 publications

Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain

Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

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