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Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses¹

Xinyan Zhao^2,*, Bo Zheng^*, Yanfang Huang^*, Dan Yang^*, Shoshana Katzman^*, Chawnshang Chang, Deborah Fowell^* and Wei-ping Zeng^3,*,

^* David H. Smith Center for Vaccine Biology and Immunology, Aab Institute for Biomedical Sciences, Department of Microbiology, George Whipple Cancer Research Laboratory, Department of Pathology and Laboratory Medicine, Department of Urology, and Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642

Th2 cytokine expression is dependent on the transcription factor GATA-3. However, the molecular interactions of GATA-3 leading to Th2 cytokine gene activation have not been well characterized. Here, we reported a number of GATA-3 associated proteins in Th2 cells, and one of such proteins Pias1 functioned as a positive transcriptional coregulator for GATA-3. When overexpressed in Th2 cells, Pias1 enhanced the expression of IL-13, and to lesser degrees, IL-4 and -5. Conversely, Pias1 siRNA down-regulated the Th2 cytokine expression. In Leishmania major infection, manipulating Pias1 expression in parasite-reactive CD4 T cells altered severity of disease caused by Th2 responses. Mechanistically, Pias1 markedly potentiated GATA-3-mediated activation of the IL-13 promoter by facilitating the recruitment of GATA-3 to the promoter. In contrast, IL-5 promoter was modestly enhanced by Pias1 and no effect was observed on IL-4 promoter. Thus, both promoter activation and additional mechanisms are responsible for regulation by Pias1.

¹ This work is partially supported by National Institutes of Health Grants R01-AI47263 to W.Z. and a Senior Researcher Award to W.Z. from Crohn’s and Colitis Foundation of America.

² Current address: Department of Microbiology, University of Pennsylvania School of Medicine, 221 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104.

³ Address correspondence and reprint requests to Dr. Wei-ping Zeng, Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Box 626, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: weiping_zheng{at}urmc.rochester.edu

⁴ Abbreviations used in this paper: HA, hemagglutinin; AD, activating domain; BD, binding domain.