title: PDLIM2 inhibits T helper 17 cell development and granulomatous inflammation through degradation of STAT3.
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.
authors.affiliation: Laboratory for Inflammatory Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan. ttanaka@rcai.riken.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Ryuta
authors.initials: R
authors.lastname: Muromoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Ikeda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sekine
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Grusby
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D006099:Granuloma / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D060588:LIM Domain Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; C502929:PDLIM2 protein, human; C508508:Pdlim2 protein, mouse; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse