Promiscuous Janus kinase binding to cytokine receptors modulates signaling efficiencies and contributes to cytokine pleiotropy

IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Science Signaling Pub Date : 2024-11-19 DOI:10.1126/scisignal.adl1892
Eyal Zoler, Thomas Meyer, Junel Sotolongo Bellón, Mia Mönnig, Boyue Sun, Jacob Piehler, Gideon Schreiber
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Abstract

Janus kinases (JAKs) bind to class I and II cytokine receptors, activating signaling and regulating gene transcription through signal transducer and activator of transcription (STAT) proteins. Type I interferons (IFNs) require the JAK members TYK2 and JAK1, which bind to the receptor subunits IFNAR1 and IFNAR2, respectively. We investigated the role of JAKs in regulating IFNAR signaling activity. Synthetic IFNARs in which the extracellular domains of IFNAR1 and IFNAR2 are replaced with nanobodies had near-native type I IFN signaling, whereas the homomeric variant of IFNAR2 initiated much weaker signaling, despite harboring docking sites for JAKs and STATs. Cells with JAK1 and TYK2 knockout (KO) showed residual signaling, suggesting partial complementation by the remaining JAKs, particularly when they were overexpressed. Live-cell micropatterning experiments confirmed the promiscuous binding of JAK1, JAK2, and TYK2 to IFNAR1 and IFNAR2, and their recruitment correlated with their relative cellular abundances. However, each JAK had a different efficacy in inducing cross-phosphorylation and downstream signaling. JAK binding was also promiscuous for other cytokine receptors, including IFN-L1, IL-10Rβ, TPOR, and GHR, but not for EPOR, which activated different downstream signaling pathways. These findings suggest that competitive binding of JAKs to cytokine receptors together with the varying absolute and relative abundances of the JAKs in different cell types can account for the cell type–dependent signaling pleiotropy of cytokine receptors.
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杂合 Janus 激酶与细胞因子受体的结合可调节信号传递效率,并促进细胞因子的多效性。
Janus 激酶(JAK)与 I 类和 II 类细胞因子受体结合,通过信号转导蛋白和转录激活蛋白(STAT)激活信号并调节基因转录。I 型干扰素(IFNs)需要 JAK 成员 TYK2 和 JAK1,它们分别与受体亚基 IFNAR1 和 IFNAR2 结合。我们研究了 JAK 在调节 IFNAR 信号活性中的作用。IFNAR1和IFNAR2的胞外结构域被纳米抗体取代的合成IFNARs具有近乎原生的I型IFN信号,而IFNAR2的同源变体启动的信号要弱得多,尽管它含有JAKs和STATs的对接位点。JAK1和TYK2基因敲除(KO)的细胞显示出残余信号,这表明剩余的JAKs具有部分互补性,尤其是当它们过表达时。活细胞微图案实验证实了 JAK1、JAK2 和 TYK2 与 IFNAR1 和 IFNAR2 的杂乱结合,它们的招募与它们在细胞中的相对丰度相关。然而,每种 JAK 在诱导交叉磷酸化和下游信号转导方面的功效各不相同。JAK 与其他细胞因子受体(包括 IFN-L1、IL-10Rβ、TPOR 和 GHR)的结合也是杂乱无章的,但与 EPOR 的结合却不会激活不同的下游信号通路。这些研究结果表明,JAK 与细胞因子受体的竞争性结合,以及 JAK 在不同细胞类型中的绝对和相对丰度的不同,可以解释细胞因子受体的信号多义性与细胞类型有关。
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来源期刊
Science Signaling
Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
CiteScore
9.50
自引率
0.00%
发文量
148
审稿时长
3-8 weeks
期刊介绍: "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.
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