Gata3/Ruvbl2 complex regulates T helper 2 cell proliferation via repression of Cdkn2c expression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 46; pp. 18626 - 18631
• Main Authors: Hosokawa, Hiroyuki, Tanaka, Tomoaki, Kato, Miki, Shinoda, Kenta, Tohyama, Hiroyuki, Hanazawa, Asami, Tamaki, Yuuki, Hirahara, Kiyoshi, Yagi, Ryoji, Sakikawa, Ikue, Morita, Atsushi, Nagira, Morio, Poyurovsky, Masha V., Suzuki, Yutaka, Motohashi, Shinichiro, Nakayama, Toshinori
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.11.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Animals; Antigens; ATPases Associated with Diverse Cellular Activities; Binding sites; Biological Sciences; Bromodeoxyuridine; CD4-positive T-lymphocytes; Cell growth; Cell lines; Cell Proliferation; Chromatin; Chromatin Immunoprecipitation; Cultured cells; cyclin-dependent kinase; Cyclin-Dependent Kinase Inhibitor p18 - metabolism; Cytokines; DNA Helicases - immunology; DNA Primers - genetics; GATA transcription factors; GATA3 Transcription Factor - immunology; Gene expression regulation; Gene Expression Regulation - immunology; Gene Knockdown Techniques; genes; Genetic loci; Immunoblotting; Immunoprecipitation; inflammation; interleukin-5; loci; Luciferases; Mass Spectrometry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecules; Multiprotein Complexes - immunology; Proteins; Real-Time Polymerase Chain Reaction; Repression; Stem cells; T cell receptors; T lymphocytes; Th2 Cells - cytology; transcriptional activation; master transcription factor; transcriptional regulation; polycomb group complex
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1311100110

GATA-binding protein 3 (Gata3) controls the differentiation of naive CD4 T cells into T helper 2 (Th2) cells by induction of chromatin remodeling of the Th2 cytokine gene loci, direct transactivation of Il5 and Il13 genes, and inhibition of Ifng . Gata3 also facilitates Th2 cell proliferation via additional mechanisms that are far less well understood. We herein found that Gata3 associates with RuvB-like protein 2 (Ruvbl2) and represses the expression of a CDK inhibitor, cyclin-dependent kinase inhibitor 2c (Cdkn2c) to facilitate the proliferation of Th2 cells. Gata3 directly bound to the Cdkn2c locus in an Ruvbl2-dependent manner. The defect in the proliferation of Gata3 -deficient Th2 cells is rescued by the knockdown of Cdkn2c , indicating that Cdkn2c is a key molecule involved in the Gata3-mediated induction of Th2 cell proliferation. Ruvbl2-knockdown Th2 cells showed decreased antigen-induced expansion and caused less airway inflammation in vivo. We therefore have identified a functional Gata3/Ruvbl2 complex that regulates the proliferation of differentiating Th2 cells through the repression of a CDK inhibitor, Cdkn2c .