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Sci. Signal., 6 December 2011
Vol. 4, Issue 202, p. ra85
[DOI: 10.1126/scisignal.2001637]

RESEARCH ARTICLES

PDLIM2 Inhibits T Helper 17 Cell Development and Granulomatous Inflammation Through Degradation of STAT3

Takashi Tanaka1*{dagger}, Yu Yamamoto2*, Ryuta Muromoto2, Osamu Ikeda2, Yuichi Sekine2, Michael J. Grusby3, Tsuneyasu Kaisho4,5, and Tadashi Matsuda2{dagger}

1 Laboratory for Inflammatory Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
2 Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
3 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
4 Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
5 Laboratory for Immune Regulation, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.

* These authors contributed equally to this work.

Abstract: Granuloma formation is an important host defense mechanism against intracellular bacteria; however, uncontrolled granulomatous inflammation is pathologic. T helper 17 (TH17) cells are thought to have a pathogenic role in autoimmune and inflammatory diseases, including in granulomas. Here, we report that the PDZ-LIM domain protein PDLIM2 inhibited TH17 cell development and granulomatous responses by acting as a nuclear ubiquitin E3 ligase that targeted signal transducer and activator of transcription 3 (STAT3), a transcription factor critical for the commitment of naïve CD4+ T cells to the TH17 lineage. PDLIM2 promoted the polyubiquitination and proteasomal degradation of STAT3, thereby disrupting STAT3-mediated gene activation. Deficiency in PDLIM2 resulted in the accumulation of STAT3 in the nucleus, enhanced the extent of TH17 cell differentiation, and exacerbated granuloma formation. This study delineates an essential role for PDLIM2 in inhibiting TH17 cell–mediated inflammatory responses by suppressing STAT3 signaling and provides a potential therapeutic target for the treatment of autoimmune diseases.

{dagger} To whom correspondence should be addressed. E-mail: ttanaka{at}rcai.riken.jp (T.T.); tmatsuda{at}pharm.hokudai.ac.jp (T.M.)

Citation: T. Tanaka, Y. Yamamoto, R. Muromoto, O. Ikeda, Y. Sekine, M. J. Grusby, T. Kaisho, T. Matsuda, PDLIM2 Inhibits T Helper 17 Cell Development and Granulomatous Inflammation Through Degradation of STAT3. Sci. Signal. 4, ra85 (2011).

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