研究人員發(fā)現(xiàn)了可抑制肉芽腫性炎癥反應(yīng)的信號通路,，該研究或可為自身免疫性疾病的治療提供新思路,，其相關(guān)論文近日發(fā)表在《科學(xué)-信號轉(zhuǎn)導(dǎo)》（Science Signaling）雜志上,。
肉芽腫的形成是機(jī)體抗細(xì)胞內(nèi)細(xì)菌的一個(gè)重要機(jī)制,，但過度的肉芽腫性炎癥反應(yīng)會(huì)對機(jī)體造成負(fù)面影響,。
輔助性T細(xì)胞17（TH17）在包括肉芽腫在內(nèi)的自身免疫和炎癥性疾病發(fā)生過程中具有重要作用,。
研究者發(fā)現(xiàn),，信號轉(zhuǎn)導(dǎo)子和轉(zhuǎn)錄激活子3（STAT3）在CD4+T細(xì)胞向TH17細(xì)胞的分化過程中起重要作用,，PDZ-LIM域蛋白PDLIM2作為核泛素E3連接酶抑制STAT3的作用，進(jìn)而抑制TH17細(xì)胞的活化聚集和肉芽腫的形成,。
PDLIM2促使STAT3聚泛素化和蛋白酶體降解,，從而破壞STAT3介導(dǎo)基因的活化,。
此外，細(xì)胞內(nèi)若缺乏PDLIM2,，則會(huì)導(dǎo)致STAT3在核內(nèi)堆積,，促使TH17細(xì)胞分化，進(jìn)而促進(jìn)肉芽腫形成,。
該研究表明,，PDLIM2在抑制TH17細(xì)胞介導(dǎo)的炎癥反應(yīng)過程中具有重要作用，它通過抑制STAT3信號發(fā)揮作用,，為自身免疫性疾病提供了治療靶點(diǎn),。（生物谷bioon.com）
doi:10.1126/scisignal.2001637
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PDLIM2 Inhibits T Helper 17 Cell Development and Granulomatous Inflammation Through Degradation of STAT3
Takashi Tanaka, Yu Yamamoto, Ryuta Muromoto, Osamu Ikeda, Yuichi Sekine, Michael J. Grusby, Tsuneyasu Kaisho, and Tadashi Matsuda.
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 na?ve 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.
