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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, Chang Hoon Lee, Moon Kyoo Jang^*, Tomohiko Tamura^*, Prafullakumar Tailor^*, Hyun Kook Cho, JaeHun Cheong, Huabao Xiong^¶, Herbert C. Morse, III and Keiko Ozato^2,*

^* Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development and Proteomics and Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases, 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

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- 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-/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.

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.

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

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

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