The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

The Journal of Immunology, 2007, 179, 26 -30
Copyright © 2007 by The American Association of Immunologists, Inc.
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kong, H. J.
Right arrow Articles by Ozato, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kong, H. J.
Right arrow Articles by Ozato, K.

Cutting Edge: Autoantigen Ro52 Is an Interferon Inducible E3 Ligase That Ubiquitinates IRF-8 and Enhances Cytokine Expression in Macrophages1

Hee Jeong Kong*,§, D. Eric Anderson{dagger}, Chang Hoon Lee{ddagger}, Moon Kyoo Jang*, Tomohiko Tamura*, Prafullakumar Tailor*, Hyun Kook Cho§, JaeHun Cheong§, Huabao Xiong, Herbert C. Morse, III{ddagger} and Keiko Ozato2,*

* Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development and {dagger} Proteomics and Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases, {ddagger} Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; § Biotechnology Research Institute, National Fisheries Research and Development Institute, Republic of Korea; and Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
IFN regulatory factor (IRF)-8 is a transcription factor important for the development and function of macrophages. It plays a critical role in the induction of cytokine genes, including IL-12p40. Immunopurification and mass spectrometry analysis found that IRF-8 interacted with Ro52 in murine macrophages upon IFN-{gamma} and TLR stimulation. Ro52 is an IFN-inducible protein of the tripartite motif (TRIM) family and is an autoantigen present in patients with Sjögren’s syndrome and systemic lupus erythematosus. Ro52 has a RING motif and is capable of ubiquitinating itself. We show that IRF-8 is ubiquitinated by Ro52 both in vivo and in vitro. Ectopic expression of Ro52 enhanced IL-12p40 expression in IFN-{gamma}/TLR-stimulated macrophages in an IRF-8-dependent manner. Together, Ro52 is an E3 ligase for IRF-8 that acts in a non-degradation pathway of ubiquitination, and contributes to the elicitation of innate immunity in macrophages.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Ubiquitination regulates many facets of innate and adaptive immune responses (1). For example, Cbl and Cbl-b ubiquitinate phosphotyrosine kinase receptors and induce their degradation, thereby inhibiting receptor-mediated signaling. Although many E3 ubiquitin ligases are involved in proteasome-mediated protein degradation, other ligases regulate biological processes unrelated to proteolysis, including transcription (2). TNFR-associated factor 6 (TRAF6),3 another E3 ligase is activated by TLR stimulation, which leads to activation of IKKbeta necessary for NF-{kappa}B functions through a non-degradation pathway (3). In addition, TRAF6 ubiquitinates IFN regulatory factor-7 (IRF-7) and enhances type I IFN induction (4). Both Cbl and TRAF6 carry the RING domain, a signature motif for a large group of E3 ligases (1). There are additional proteins that carry a RING domain, but whose E3 ligase activity and target substrates have not been documented, including proteins of the tripartite motif (TRIM) family (5, 6). TRIM proteins have, in addition to the RING domain, several other structurally related domains (see Fig. 2 for diagram). Ro52, TRIM21, also called SSA, has long been known as an autoantigen present in patients with autoimmune diseases including Sjögren’s syndrome and systemic lupus erythematosus (7). It is a broadly expressed 52-kDa protein, and the expression is induced by IFN-{gamma} in macrophages (8). Despite its well known autoantigen status, the biological function of Ro52 has remained elusive. Recent reports show that Ro52 has an autoubiquitination activity, suggesting a role in a ubiquitination pathway, although substrates catalyzed by Ro52 have yet to be identified (9, 10). IRF-8 is a transcription factor that regulates the development and function of macrophages, dendritic cells and B cells (11, 12, 13). It plays a critical role in the expression of proinflammatory cytokines including IL-12p40 and type I IFN genes (11, 14, 15). IRF-8 is induced by IFN-{gamma} in macrophages in synergy with TLR signaling (16). Here we report that Ro52 interacts with IRF-8 in IFN-{gamma}/TLR-stimulated macrophages, causing IRF-8 ubiquitination. Rather than prompting its degradation, Ro52 enhanced the ability of IRF-8 to stimulate IL-12p40 expression. By facilitating transcriptional activity of IRF-8, Ro52 may play a significant role in regulating host defense responses in macrophages.


Figure 2
View larger version (28K):
[in this window]
[in a new window]

  		FIGURE 2. Analysis of interaction domains. A, Ro52-GST or GST alone bound to glutathione beads was incubated with 35S-labeled, in vitro translated wild-type or truncated IRF-8, and bound materials were detected by autoradiography. DBD and IAD stand for the DNA binding domain and IRF association domain, respectively. B, IRF-8-GST or GST alone was incubated with 35S-lableled wild-type or truncated Ro52. RING represents the E3 ligase motif and cc the coiled-coil domain, respectively. C, Bifluorescence complementation analysis. RAW cells were transfected with plasmids for IRF-8-YC, YN-Ro52 and HcRed. YFP and HcRed signals were viewed on a Leica Sp2 confocal microscope.

 

   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Plasmids and vectors

Murine Ro52 cDNAs were cloned into appropriate restriction sites of pcDNA3.1/(+), pEGFP-C1, and pMSCV-CD8t vectors (11, 17).

Purification of IRF-8 immune complex and interaction assays

RAW 264.7 (hereafter RAW) cells were cultured as described by Xiong et al. (17) and stimulated with 100 U/ml IFN-{gamma} (PeproTech) overnight followed by 100 ng/ml CpG DNA for 4 h (11). Nuclear extracts were prepared from ~109 RAW cells in buffer containing 20 mM HEPES (pH 7.9), 0.3 M KCl, 1.5 mM MgCl2, 25% glycerol, 0.2 mM EDTA, 0.5 mM DTT, and protease inhibitors and precipitated with anti-IRF-8 Ab (18). Bound proteins were eluted with 20 mM HEPES buffer (pH 7.5) containing 1% sarcosyl, separated on NuPAGE and stained with colloidal blue. Mass spectrometry was performed in the Proteomics and Mass Spectrometry Facility of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. GST pull-down assays and bifluorescence complementation analysis were performed as described (18, 19).

Ubiquitination assays

Recombinant E1 (100 nM), and E2 (250 nM), purified ubiquitin (34 µM) (all obtained from Boston Biochem) and IRF-8 (200 ng) were incubated with GST-Ro52 in 20 µl of buffer, and fractionated reaction mixtures were analyzed by immunoblot assay. 293T cells were transfected with indicated plasmids using Lipofectamine-PLUS (Invitrogen Life Technologies) or PolyFect (Qiagen) for 48 h and treated with MG-132 (25 µM) for 2 h before harvest. Extracts were immunoprecipitated and analyzed by immunoblot.

Retroviral transduction

RAW and CL-2 (14) macrophages were transduced with pMCV-CD8t viral vectors as described (11, 17). Cells were stimulated with IFN-{gamma} and CpG (IFN-{gamma}/CpG) and samples were tested in quantitative RT-PCR, ELISA, and immunoblot assays (11). Primer sequences used in this work are available upon request.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Interaction of IRF-8 with Ro52 in stimulated macrophages

To identify IRF-8-interacting proteins in activated macrophages, IRF-8 complexes were immunopurified from nuclear extracts from RAW cells stimulated with IFN-{gamma} and CpG (IFN-{gamma}/CpG). Immune complexes were analyzed by tandem mass spectrometry. Several bands migrated above IRF-8 in Fig. 1A contained peptides corresponding to murine Ro52 (Fig. 1B). IRF-8 immune complexes also contained TEL, an Ets family protein previously shown to interact with IRF-8, supporting the validity of our procedure (18). The IRF-8/Ro52 interaction was confirmed by immunoprecipitation and immunoblot analysis of independent samples (Fig. 1C). IRF-8 immune precipitates, but not preimmune precipitates, contained a ~52-kDa protein that reacted with the Ab specific for Ro52. Ro52 was reported to predominantly localize to the cytoplasm and less to the nucleus (8, 9). In agreement, immunoblot analysis of fractionated extracts in Fig. 1D revealed high and low levels of Ro52 in the cytoplasmic and nuclear fractions, respectively. Given that IRF-8 complexes were purified from nuclear extracts, these data suggested that IRF-8 interacted with Ro52 in the nucleus after IFN-{gamma}/CpG stimulation (the notion corroborated in Fig. 2C). Unstimulated RAW cells expressed Ro52 and IRF-8 only at low levels, in which IRF-8 immune complexes did not contain appreciable amounts of Ro52. Samples stimulated with IFN-{gamma} alone also contained Ro52, although the amounts were less than those found in samples stimulated with IFN-{gamma}/CpG, presumably reflecting synergistic induction of IRF-8 by the two stimuli (16).


Figure 1
View larger version (21K):
[in this window]
[in a new window]

  		FIGURE 1. Mass spectrometry analysis of IRF-8 immune complexes. A, Nuclear extracts from IFN-{gamma}/CpG-stimulated RAW cells were precipitated with preimmune Ig (Pre-I) or anti-IRF-8 Ab, resolved on Nu-PAGE. Proteins identified by mass spectrometry are indicated by bars. B, Ro52 peptides found in the IRF-8 complexes. The numbers indicate amino acid positions. C, Extracts from stimulated RAW cells were immunoprecipitated (IP) and immunoblotted (IB) with the indicated Abs. D, Cytoplasmic (Cyto) and nuclear (Nuc) fractions from stimulated RAW cells were immunoblotted for Ro52 and IRF-8. c-Cbl and the TATA-binding protein (TBP) were tested to confirm the purity of each fraction.

 
Domain analysis for the IRF-8/Ro52 interaction

IRF-8 is composed of the N-terminal DNA binding domain (DBD), a linker region and the C-terminal IRF association domain (IAD) (Fig. 2A) (12). Ro52, similar to other TRIM family proteins, contains four distinct domains (Fig. 2B) (5, 6). To study domains important for the interaction, GST pull-down assays were performed. In Fig. 2A, GST-Ro52 bound to full-length IRF-8 and a series of truncated versions except for {Delta}C. Conversely, GST-IRF-8 bound to full-length Ro52 and N-terminal truncations but not C-terminal truncations. These results indicate that the interaction requires the linker region of IRF-8 and the B30.2/SPRY domain of Ro52. The interaction of IRF-8 with Ro52 through the C-terminal region was also observed in coimmunoprecipitation assay (not shown).

Nuclear interaction of Ro52 with IRF-8

To verify an in vivo interaction of IRF-8 with Ro52, we performed bifluorescence complementation analysis (20). This method relies on the complementation of yellow fluorescence protein (YFP) fluorescent signals driven by a protein-protein interaction. With this method, real time protein-protein interactions can be visualized in a specific intracellular site in live cells. Wild-type or truncated Ro52 fused to the N-terminal YFP fragment (YN-Ro52 in Fig. 2C) were cotransfected along with full-length IRF-8 fused to the C-terminal YFP fragment (IRF-8-YC) into RAW cells. Wild-type Ro52 and {Delta}R (1–160) gave abundant YFP signals in the nucleus. The predominantly nuclear complementation was evident as judged by cytoplasmic and nuclear localization of cotransfected HcRed protein (Fig. 2C, middle panel). Ro52 (160–470), in contrast, did not show complementation. Similarly transfection of YN-Ro52 or IRF-8-YC alone did not produce YFP signals. Transfection efficiency was monitored by counting HcRed positive cells (20). Approximately 30–40% of transfected cells were HcRed positive, irrespective of Ro52, IRF-8 transfection or YFP complementation. In cells cotransfected with both Ro52 and IRF-8, ~40–50% of HcRed-positive cells emitted detectable YFP signals. As expected, no YFP positive cells were found in HcRed-negative cell populations. In a separate transfection assay, we confirmed that wild-type and truncated Ro52 were expressed at comparable levels (not shown). These results are in agreement with data in Figs. 1 and 2 and show that Ro52 interacts with IRF-8 in the nucleus of live macrophages.

Ubiquitination of IRF-8 by Ro52 in vitro and in vivo

To examine whether IRF-8 is ubiquitinated in macrophages, IRF-8 immune precipitates from IFN-{gamma}/CpG-stimulated RAW cells were tested for reactivity with anti-ubiquitin Ab by immunoblot (Fig. 3A). Anti-IRF-8 Ab precipitates, but not preimmune precipitates, revealed abundant ubiquitin moieties when incubated with the proteasome inhibitor, MG-132. IRF-8 complexes precipitated from unstimulated cells also showed ubiquitin reactivity, albeit to a lesser extent. These data indicate that IRF-8 is ubiquitinated in macrophages, and the process is strongly augmented upon IFN-{gamma}/CpG stimulation. We next tested whether Ro52 ubiquitinates IRF-8 in vitro. In Fig. 3B, recombinant IRF-8 was ubiquitinated when incubated with wild-type Ro52-GST, ubiquitin, and E1 and E2 (H5a) enzymes, but not when incubated with {Delta}R, lacking the RING catalytic domain. Wild-type Ro52 was also ubiquitinated in the same reactions, indicating autoubiquitination as reported (9, 10). Next, we studied in vivo ubiquitination of IRF-8 by Ro52 (Fig. 3C). 293T cells were transfected with appropriately tagged IRF-8, ubiquitin, and increasing amounts of Ro52 and precipitated IRF-8 was tested for ubiquitination. IRF-8 was ubiquitinated in the presence of wild-type Ro52 in a dose-dependent manner. Although {Delta}C, lacking the IRF-8 interaction domain did not ubiquitinate IRF-8, {Delta}R moderately increased IRF-8 ubiquitination. The latter results may be due to the trimerization of {Delta}R with endogenous Ro52 (21). These data indicate that Ro52 ubiquitinates IRF-8 through a direct protein-protein interaction.


Figure 3
View larger version (18K):
[in this window]
[in a new window]

  		FIGURE 3. IRF-8 ubiquitination in vivo and in vitro. A, RAW cells were stimulated with IFN-{gamma}/CpG and with MG-132 for the last 2 h. Extracts were precipitated with indicated Ig and blotted with anti-ubiquitin Ab. In the bottom panels, total extracts were blotted with Ab for IRF-8 or TFIIB. B, Baculovirus recombinant IRF-8 was incubated with E1, E2, and GST-fused wild-type Ro52 or {Delta}R, and ubiquitin in the presence of ATP for 60 min at 37°C. Reaction mixtures were blotted with indicated Ab. rIRF-8 and * indicate un-ubiquitinated IRF-8 and nonspecific reaction, respectively. C, 293T cells were transfected with HA-tagged ubiquitin (HA-Ub), increasing amounts (0.2–0.6 µg) of GFP wild-type Ro52 or 0.6 µg of {Delta}R (160–470, left panel) or {Delta}C (1–160, right panel) and Flag-IRF-8 for 48 h. Extracts were immunoprecipitated with anti-Flag Ab and blotted with indicated Ab.

 
Ro52 enhancement of IL-12p40 expression

To address the biological significance of Ro52-mediated IRF-8 ubiquitination, we examined the role of Ro52 in IL-12p40 induction. IL-12p40 is a cytokine important for innate immunity and is induced in macrophages upon IFN-{gamma}/TLR stimulation (22). We previously showed that this induction required IRF-8, and consequently, CL-2, a macrophage line from IRF-8 –/– mice, failed to express IL-12p40 (14, 15). Here we tested the effect of ectopic Ro52 expression in RAW (IRF-8+/+) and CL-2 (IRF-8–/–) cells. In Fig. 4, A and B, ectopic Ro52 expression in RAW cells significantly enhanced IL-12p40 transcripts, and the protein expression upon IFN-{gamma}/CpG stimulation. On the other hand, {Delta}R and {Delta}C did not enhance IL-12p40 expression and appeared to slightly reduce the expression, suggesting a dominant-negative effect. In contrast, no IL-12p40 induction was observed in CL-2 cells, regardless of ectopic Ro52 expression. As expected, IRF-8 expression was enhanced after IFN-{gamma}/CpG stimulation in RAW cells, whereas no IRF-8 expression was seen in CL-2 cells (Fig. 4C). Also as expected, Ro52 expression was increased both in RAW and CL-2 cells upon vector introduction and after IFN-{gamma}/CpG stimulation, indicating that the lack of IL-12p40 induction in CL-2 cells was not due to lack of response to IFN-{gamma}/CpG, but due to lack of IRF-8 (Fig. 4D). Thus, ectopic Ro52 augmented IL-12p40 expression in an IRF-8-dependent manner, suggesting that ubiquitination of IRF-8 facilitates its transcriptional activity rather than facilitating degradation. Supporting this interpretation, ectopic Ro52 expression did not alter IRF-8 protein levels in RAW cells before and after stimulation for at least 24 h (Fig. 4E, and data not shown).


Figure 4
View larger version (22K):
[in this window]
[in a new window]

  		FIGURE 4. Enhancement of IL-12p40 expression by ectopic Ro52. A and B, RAW (IRF-8+/+) and CL-2 (IRF-8–/–) cells were transduced with indicated Ro52 vectors, stimulated with IFN-{gamma}/CpG. IL-12p40 transcripts and the protein were measured by quantitative RT-PCR and ELISA, respectively. C and D, Expression of IRF-8 and Ro52 was measured by quantitative RT-PCR using primers for IRF-8, {Delta}R or {Delta}C. The latter two also detected wild-type Ro52 transcripts. E, Extracts from above cells were immunoblotted for IRF-8 and TFIIB.

 
In this study we identified Ro52, an E3 ubiquitin ligase of the TRIM family, as an interacting partner of IRF-8 and showed that it ubiquitinated IRF-8 in vivo and in vitro. Increased Ro52 led to enhanced expression of a target gene IL-12p40 rather than promoting IRF-8 degradation. Our results add IRF-8 to a growing list of transcription factors that gain enhanced transcriptional activity upon ubiquitination (2, 4, 23). Although the mechanism by which ubiquitination enhances transcription remains elusive, ubiquitination may control dynamic assembly/disassembly of transcription factors at the promoters. Although the mechanisms are unclear, it seems clear that Ro52 ubiquitination of IRF-8 is tightly linked to IFN-{gamma} signaling, because both Ro52 and IRF-8 are induced by the cytokine. It is worth noting that other ubiquitination events are also linked to immunological signaling. Ubiquitin ligase activity of TRAF6 is triggered by TLR signals, resulting in enhanced NF-{kappa}B and IRF-7 activity and gene expression (2, 3, 4). It is likely that IFN/TLR signaling activates multiple ubiquitin ligases, creating a complex ubiquitination network that impacts on the course of innate immune responses. We previously noted that IRF-8 is ubiquitinated by Cbl, leading to IRF-8 destabilization (17). This destabilization may be part of a postactivation event that prompts timely attenuation of potentially harmful proinflammatory responses, analogous to PIN-1-induced IRF-3 destabilization (24). Last, it has been reported that Ro52 expression is elevated in PBMC of patients with autoimmune diseases, presumably in association with increased autoantibody production and worsening diseases processes (9). Given that increased Ro52 expression would increase IRF-8 ubiquitination and cytokine gene expression potentially causing excessive inflammatory responses, IRF-8 ubiquitination reported here may contribute to autoimmune disease processes. Increased Ro52 expression in B cells may also cause an altered ubiquitination status of IRF-8, also influencing disease processes, because IRF-8 regulates B cell growth, differentiation, and function (13).


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by the Intramural Programs of National Institute of Child Health and Human Development, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institute of Allergy and Infectious Diseases, National Institutes of Health. Back

2 Address correspondence and reprint requests to Dr. Keiko Ozato, Laboratory of Molecular Growth Regulation, GDP, National Institute of Child Health and Human Development, National Institutes of Health, Building 6, Room 2A01, 6 Center Drive, Bethesda, MD 20892-2753. E-mail address: ozatok{at}nih.gov Back

3 Abbreviations used in this paper: TRAF, IRF, IFN regulatory factor; TRIM, tripartite motif; YFP, yellow fluorescent protein. Back

Received for publication March 16, 2007. Accepted for publication May 1, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

  1. Liu, Y.-C.. 2004. Ubiquitin ligases and the immune system. Annu. Rev. Immunol. 22: 81-127. [Medline]
  2. Ben-Neriah, Y.. 2002. Regulatory function of ubiquitination in the immune system. Nat. Immunol. 3: 20-26. [Medline]
  3. Deng, L., C. Wang, E. Spencer, L. Yang, A. Braun, J. You, C. Slaughter, C. Pickart, Z. J. Chen. 2000. Activation of the I{kappa}B kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103: 351-361. [Medline]
  4. Kawai, T., S. Sato, K. J. Ishii, C. Coban, H. Hemmi, M. Yamamoto, K. Terai, M. Matsuda, J. Inoue, S. Uematsu, et al 2004. Interferon-{alpha} induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5: 1061-1068. [Medline]
  5. Reymond, A., G. Meroni, A. Fantozzi, G. Merla, S. Cairo, L. Luzi, D. Riganelli, E. Zanaria, S. Messali, S. Cainarca, et al 2001. The tripartite motif family identifies cell compartments. EMBO J. 20: 2140-2151. [Medline]
  6. Nisole, S., J. P. Stoye, A. Saib. 2005. TRIM family proteins: retroviral restriction and antiviral defence. Nat. Rev. Microbiol. 3: 799-808. [Medline]
  7. Ben-Chetrit, E., E. K. Chan, K. F. Sullivan, E. M. Tan. 1988. A 52-kD protein is a novel component of the SS-A/Ro antigenic particle. J. Exp. Med. 167: 1560-1571. [Abstract/Free Full Text]
  8. Rhodes, D. A., G. Ihrke, A. T. Reinicke, G. Malcherek, M. Towey, D. A. Isenberg, J. Trowsdale. 2002. The 52 000 MW Ro/SS-A autoantigen in Sjogren’s syndrome/systemic lupus erythematosus (Ro52) is an interferon-{gamma} inducible tripartite motif protein associated with membrane proximal structures. Immunology 106: 246-256. [Medline]
  9. Espinosa, A., W. Zhou, M. Ek, M. Hedlund, S. Brauner, K. Popovic, L. Horvath, T. Wallerskog, M. Oukka, F. Nyberg, et al 2006. The Sjogren’s syndrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death. J. Immunol. 176: 6277-6285. [Abstract/Free Full Text]
  10. Wada, K., T. Kamitani. 2006. Autoantigen Ro52 is an E3 ubiquitin ligase. Biochem. Biophys. Res. Commun. 339: 415-421. [Medline]
  11. Tamura, T., P. Tailor, K. Yamaoka, H. J. Kong, H. Tsujimura, J. J. O’Shea, H. Singh, K. Ozato. 2005. IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J. Immunol. 174: 2573-2581. [Abstract/Free Full Text]
  12. Ozato, K., T. Kubota, and P. Tailor. 2007. The interferon regulatory factor family in host defense: the mechanism of action (review) J. Biol. Chem. In press.
  13. Lee, C. H., M. Melchers, H. Wang, T. A. Torrey, R. Slota, C. F. Qi, J. Y. Kim, P. Lugar, H. J. Kong, L. Farrington, et al 2006. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J. Exp. Med. 203: 63-72. [Abstract/Free Full Text]
  14. Wang, I. M., C. Contursi, A. Masumi, X. Ma, G. Trinchieri, K. Ozato. 2000. An IFN-{gamma}-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165: 271-279. [Abstract/Free Full Text]
  15. Tsujimura, H., T. Tamura, C. Gongora, J. Aliberti, C. Reis e Sousa, A. Sher, K. Ozato. 2003. ICSBP/IRF-8 retrovirus transduction rescues dendritic cell development in vitro. Blood 101: 961-969. [Abstract/Free Full Text]
  16. Kantakamalakul, W., A. D. Politis, S. Marecki, T. Sullivan, K. Ozato, M. J. Fenton, S. N. Vogel. 1999. Regulation of IFN consensus sequence binding protein expression in murine macrophages. J. Immunol. 162: 7417-7425. [Abstract/Free Full Text]
  17. Xiong, H., H. Li, H. J. Kong, Y. Chen, J. Zhao, S. Xiong, B. Huang, H. Gu, L. Mayer, K. Ozato, J. C. Unkeless. 2005. Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression. J. Biol. Chem. 280: 23531-23539. [Abstract/Free Full Text]
  18. Kuwata, T., C. Gongora, Y. Kanno, K. Sakaguchi, T. Tamura, T. Kanno, V. Basrur, R. Martinez, E. Appella, T. Golub, K. Ozato. 2002. Gamma interferon triggers interaction between ICSBP (IRF-8) and TEL, recruiting the histone deacetylase HDAC3 to the interferon-responsive element. Mol. Cell Biol. 22: 7439-7448. [Abstract/Free Full Text]
  19. Laricchia-Robbio, L., T. Tamura, T. Karpova, B. L. Sprague, J. G. McNally, K. Ozato. 2005. Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages. Proc. Natl. Acad. Sci. USA 102: 14368-14373. [Abstract/Free Full Text]
  20. Hu, C. D., T. K. Kerppola. 2003. Simultaneous visualization of multiple protein interactions in living cells using multicolor fluorescence complementation analysis. Nat Biotechnol. 21: 539-545. [Medline]
  21. Javanbakht, H., W. Yuan, D. F. Yeung, B. Song, F. Diaz-Griffero, Y. Li, X. Li, M. Stremlau, J. Sodroski. 2006. Characterization of TRIM5{alpha} trimerization and its contribution to human immunodeficiency virus capsid binding. Virology 353: 234-246. [Medline]
  22. Trinchieri, G.. 2003. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3: 133-146. [Medline]
  23. Dhananjayan, S. C., A. Ismail, Z. Nawaz. 2005. Ubiquitin and control of transcription. Essays Biochem. 41: 69-80. [Medline]
  24. Saitoh, T., A. Tun-Kyi, A. Ryo, M. Yamamoto, G. Finn, T. Fujita, S. Akira, N. Yamamoto, K. P. Lu, S. Yamaoka. 2006. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat. Immunol. 7: 598-605. [Medline]



This article has been cited by other articles:


Home page
 J. Immunol.Home page
J. X. Zhou, C. H. Lee, C. F. Qi, H. Wang, Z. Naghashfar, S. Abbasi, and H. C. Morse III
IFN Regulatory Factor 8 Regulates MDM2 in Germinal Center B Cells
J. Immunol., September 1, 2009; 183(5): 3188 - 3194.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
A. Espinosa, V. Dardalhon, S. Brauner, A. Ambrosi, R. Higgs, F. J. Quintana, M. Sjostrand, M.-L. Eloranta, J. Ni Gabhann, O. Winqvist, et al.
Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway
J. Exp. Med., August 3, 2009; 206(8): 1661 - 1671.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
S. Bolland and A. Garcia-Sastre
Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice
J. Exp. Med., August 3, 2009; 206(8): 1647 - 1651.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. Yoshimi, T.-H. Chang, H. Wang, T. Atsumi, H. C. Morse III, and K. Ozato
Gene Disruption Study Reveals a Nonredundant Role for TRIM21/Ro52 in NF-{kappa}B-Dependent Cytokine Expression in Fibroblasts
J. Immunol., June 15, 2009; 182(12): 7527 - 7538.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
T. Kawai and S. Akira
The roles of TLRs, RLRs and NLRs in pathogen recognition
Int. Immunol., April 1, 2009; 21(4): 317 - 337.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. Yang, H.-X. Shi, X.-Y. Liu, Y.-F. Shan, B. Wei, S. Chen, and C. Wang
TRIM21 Is Essential to Sustain IFN Regulatory Factor 3 Activation during Antiviral Response
J. Immunol., March 15, 2009; 182(6): 3782 - 3792.
[Abstract] [Full Text] [PDF]

Home page
 J. Gen. Virol.Home page
P. Eldin, L. Papon, A. Oteiza, E. Brocchi, T. G. Lawson, and N. Mechti
TRIM22 E3 ubiquitin ligase activity is required to mediate antiviral activity against encephalomyocarditis virus
J. Gen. Virol., March 1, 2009; 90(3): 536 - 545.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Y. Kim and K. Ozato
The Sequestosome 1/p62 Attenuates Cytokine Gene Expression in Activated Macrophages by Inhibiting IFN Regulatory Factor 8 and TNF Receptor-Associated Factor 6/NF-{kappa}B Activity
J. Immunol., February 15, 2009; 182(4): 2131 - 2140.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. Higgs, J. N. Gabhann, N. B. Larbi, E. P. Breen, K. A. Fitzgerald, and C. A. Jefferies
The E3 Ubiquitin Ligase Ro52 Negatively Regulates IFN-{beta} Production Post-Pathogen Recognition by Polyubiquitin-Mediated Degradation of IRF3
J. Immunol., August 1, 2008; 181(3): 1780 - 1786.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. Miyajima, S. Maruyama, M. Bohgaki, S. Kano, M. Shigemura, N. Shinohara, K. Nonomura, and S. Hatakeyama
TRIM68 Regulates Ligand-Dependent Transcription of Androgen Receptor in Prostate Cancer Cells
Cancer Res., May 1, 2008; 68(9): 3486 - 3494.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
T. Schaller, S. Hue, and G. J. Towers
An Active TRIM5 Protein in Rabbits Indicates a Common Antiviral Ancestor for Mammalian TRIM5 Proteins
J. Virol., November 1, 2007; 81(21): 11713 - 11721.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kong, H. J.
Right arrow Articles by Ozato, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kong, H. J.
Right arrow Articles by Ozato, K.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS