Synthetic Heterodimers of Type III Interferon Receptors Require TYK2 for STAT Activation.

IF 1.9 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Emily V Mesev, Emma G Guare, Alexander Ploss, Jared E Toettcher
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引用次数: 0

Abstract

Type III interferons (IFN-λ) are central to host defense against viral infection of epithelial barrier surfaces. IFN-λ binding to its receptor induces a JAK-STAT cascade through kinases Janus-associated kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which are associated on either subunit of the heterodimeric type III IFN receptor. Recent studies have shown that TYK2 is not necessary for IFN-λ to signal, in contrast to IFN-α, which uses the same JAK-STAT pathway activated by the type I IFN receptor. The mechanism for this differential TYK2 requirement is unknown. Our study uses synthetic IFN receptors in TYK2-deficient U2OS epithelial cells to define the processes in type I and III IFN signaling that require TYK2. We find that TYK2 deficiency reduces signaling equally from heterodimers of either type I or III IFN receptor intracellular domains. In contrast, JAK1-associated homodimers of IFNAR2 or IFNLR1 are both fully signaling competent even in the absence of TYK2. These results suggest that heterodimerization of the type III IFN receptor is insufficient to confer TYK2-independent signaling. Thus, we propose that noncanonical receptor complexes may participate in endogenous type III IFN signaling to confer TYK2-independent signaling downstream of IFN-λ stimulation.

III型干扰素受体的合成杂二聚体需要TYK2来激活STAT。
III型干扰素(IFN-λ)是宿主防御上皮屏障表面病毒感染的核心。IFN-λ与其受体的结合通过激酶Janus相关激酶1(JAK1)和酪氨酸激酶2(TYK2)诱导JAK-STAT级联,这两种激酶与异二聚体III型IFN受体的任一亚基相关。最近的研究表明,TYK2不是IFN-λ发出信号所必需的,而IFN-α使用由I型IFN受体激活的相同JAK-STAT途径。这种差分TYK2要求的机制尚不清楚。我们的研究使用TYK2缺陷U2OS上皮细胞中的合成IFN受体来确定需要TYK2的I型和III型IFN信号传导过程。我们发现TYK2缺乏同样减少了来自I型或III型IFN受体胞内结构域的异二聚体的信号传导。相反,即使在不存在TYK2的情况下,IFNAR2或IFNLR1的JAK1相关同源二聚体都是完全信号传导能力的。这些结果表明III型IFN受体的异二聚化不足以赋予TYK2独立的信号传导。因此,我们提出非经典受体复合物可能参与内源性III型IFN信号传导,从而在IFN-λ刺激的下游赋予TYK2独立信号传导。
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来源期刊
CiteScore
3.80
自引率
0.00%
发文量
78
审稿时长
2.2 months
期刊介绍: Journal of Interferon & Cytokine Research (JICR) provides the latest groundbreaking research on all aspects of IFNs and cytokines. The Journal delivers current findings on emerging topics in this niche community, including the role of IFNs in the therapy of diseases such as multiple sclerosis, the understanding of the third class of IFNs, and the identification and function of IFN-inducible genes.
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