Hummel Thorben M, Ackfeld Theresa, Schönberg Marco, Ciupka Gregor, Schulz Falk, Oberdoerster Anne, Grötzinger Joachim, Scheller Jürgen, Floss Doreen M
Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Institute of Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany.
Mol Cell Biol. 2017 Aug 11;37(17). doi: 10.1128/MCB.00014-17. Print 2017 Sep 1.
Interleukin 23 (IL-23) regulates the development of TH17 cells, which are important for antimicrobial and antifungal responses and autoimmune and chronic inflammatory diseases. IL-23-induced Jak/STAT signaling is mediated via the heterodimeric IL-23 receptor (IL-23R)-IL-12 receptor β1 (IL-12Rβ1) complex. The typical signal-transducing receptor of the IL-6/IL-12 family contains three extracellular-membrane-proximal fibronectin type III (FNIII) domains, which are not involved in cytokine binding but are mandatory for signal transduction. In place of FNIII-type domains, IL-23R has a structurally undefined stalk. We hypothesized that the IL-23R stalk acts as a spacer to position the cytokine binding domains at a defined distance from the plasma membrane to enable signal transduction. Minor deletions of the murine, but not of the human, IL-23R stalk resulted in unresponsiveness to IL-23. Complete deletion of the human IL-23R stalk and the extended murine IL-23R stalk, including a 20-amino-acid-long duplication of domain 3, however, induced ligand-independent, autonomous receptor activation, as determined by STAT3 phosphorylation and cell proliferation. Ligand-independent, autonomous activity was caused by IL-23R homodimers and was independent of IL-12Rβ1. Our data show that deletion of the stalk results in biologically active IL-23R homodimers, thereby creating an as-yet-undescribed receptor complex of the IL-6/IL-12 cytokine family.
白细胞介素23（IL-23）调节TH17细胞的发育，TH17细胞对抗菌和抗真菌反应以及自身免疫和慢性炎症性疾病很重要。IL-23诱导的Jak/STAT信号传导是通过异二聚体IL-23受体（IL-23R）-IL-12受体β1（IL-12Rβ1）复合物介导的。IL-6/IL-12家族的典型信号转导受体包含三个细胞外膜近端III型纤连蛋白（FNIII）结构域，这些结构域不参与细胞因子结合，但对信号转导是必需的。IL-23R没有FNIII型结构域，而是有一个结构未明的柄部。我们推测IL-23R柄部作为一个间隔物，将细胞因子结合结构域定位在距质膜一定距离处，以实现信号转导。小鼠IL-23R柄部的微小缺失会导致对IL-23无反应，但人类IL-23R柄部的微小缺失则不会。然而，人类IL-23R柄部的完全缺失以及延长的小鼠IL-23R柄部（包括结构域3的20个氨基酸的重复）会诱导配体非依赖性的自主受体激活，这通过STAT3磷酸化和细胞增殖来确定。配体非依赖性的自主活性是由IL-23R同二聚体引起的，且不依赖于IL-12Rβ1。我们的数据表明，柄部的缺失会产生具有生物活性的IL-23R同二聚体，从而形成IL-6/IL-12细胞因子家族一个尚未描述的受体复合物。
