2026-05-25 理化学研究所
図1 PDLIM4による転写因子STATの不活性化の分子メカニズム
ヘルパーT細胞は、侵入した病原体の種類に応じて「STAT4」、「STAT6」および「STAT3」を活性化し、それぞれTh1、Th2、Th17細胞という特殊なT細胞に分化する。他方、PDLIM4は、細胞質内においてタンパク質チロシン脱リン酸化酵素（PTP-BL）と結合し、これをSTAT4、STAT6、STAT3に呼び寄せて、STAT4、STAT6、STAT3の活性化に必要なリン酸化を抑制することにより、これらを不活性化する。サイトカイン：細胞同士の情報伝達に関わるさまざまな生理活性を持つタンパク質の総称。生体防御に関与する多種類の細胞に働き、免疫反応を発動する。JAKs：ヤヌスキナーゼ（リン酸化酵素）。P：リン酸基。
＜関連情報＞
- https://www.riken.jp/press/2026/20260525_3/index.html
- https://academic.oup.com/intimm/advance-article/doi/10.1093/intimm/dxag019/8661778
PDLIM4はPTP-BLをリクルートすることでSTAT転写因子の脱リン酸化を促進し、Th1、Th2、およびTh17細胞の分化を阻害する PDLIM4 promotes dephosphorylation of STAT transcription factors by recruiting PTP-BL and inhibits Th1, Th2, and Th17 cell differentiation
Aya Jodo,Masakiyo Nakahira,Yuta Kochi,Akiko Sugimoto-Ishige,Tsuneyasu Kaisho,Takashi Tanaka
International immunology Published:25 May 2026
DOI:https://doi.org/10.1093/intimm/dxag019
Abstract
STAT (signal transducers and activators of transcription) transcription factors are activated by tyrosine phosphorylation after cytokine stimulation and are critical for the differentiation of T-helper (Th) cells into particular Th lineage subsets. How STAT-mediated Th cell differentiation is negatively regulated, however, is not fully understood. Here, we report that PDLIM4 binds to STAT3, 4, and 6 and suppresses gene activation mediated by these STATs. PDLIM4 acts as an adaptor that recruits PTP-BL, a protein tyrosine phosphatase, through its LIM (abnormal cell lineage 11-islet 1-mechanosensory abnormal 3) domain, facilitating dephosphorylation of STAT proteins. PDLIM4-deficiency in CD4+ T cells resulted in augmented tyrosine phosphorylation of these STAT proteins and consequently enhanced Th1, Th2, and Th17 cell differentiation, suggesting that PDLIM4 regulates the differentiation of multiple lineages of Th cells by suppressing STAT signaling. We further found that a non-synonymous single-nucleotide polymorphism in PDLIM4, which causes the substitution of a glycine residue with a cysteine in the LIM domain, is associated with susceptibility to rheumatoid arthritis and Graves’ disease, both of which are known to be Th17 cell-driven autoimmune diseases. Notably, PDLIM4 containing this amino acid substitution in the LIM domain showed reduced binding to PTP-BL and was therefore partially impaired in its ability to dephosphorylate STAT3 and suppress STAT3 signaling. Our findings define an essential role of PDLIM4 in negatively regulating STAT-mediated Th-cell differentiation and preventing the onset of human autoimmune diseases.
