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PDLIM2 inhibits T helper 17 cell development and granulomatous inflammation through degradation of STAT3.
- Source :
-
Science signaling [Sci Signal] 2011 Dec 06; Vol. 4 (202), pp. ra85. Date of Electronic Publication: 2011 Dec 06. - Publication Year :
- 2011
-
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.
- Subjects :
- Adaptor Proteins, Signal Transducing deficiency
Adaptor Proteins, Signal Transducing genetics
Animals
Base Sequence
Cell Differentiation
Cell Line
Granuloma etiology
Granuloma metabolism
HEK293 Cells
Humans
Inflammation etiology
Inflammation metabolism
LIM Domain Proteins antagonists & inhibitors
LIM Domain Proteins deficiency
LIM Domain Proteins genetics
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Microfilament Proteins antagonists & inhibitors
Microfilament Proteins genetics
Microfilament Proteins immunology
Microfilament Proteins physiology
RNA, Small Interfering genetics
Signal Transduction immunology
Signal Transduction physiology
Th17 Cells cytology
Ubiquitination
Adaptor Proteins, Signal Transducing immunology
Adaptor Proteins, Signal Transducing physiology
Granuloma immunology
Inflammation immunology
LIM Domain Proteins immunology
LIM Domain Proteins physiology
STAT3 Transcription Factor metabolism
Th17 Cells immunology
Th17 Cells physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1937-9145
- Volume :
- 4
- Issue :
- 202
- Database :
- MEDLINE
- Journal :
- Science signaling
- Publication Type :
- Academic Journal
- Accession number :
- 22155789
- Full Text :
- https://doi.org/10.1126/scisignal.2001637