Comparable potency of IFNα2 and IFNß on immediate JAK/STAT activation but differential down-regulation of IFNAR2
Comparable potency of IFNα2 and IFNß on immediate JAK/STAT activation but differential down-regulation of IFNAR2
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DOI：
10.1042/bj20070605
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发表时间：
2007-10-01
影响因子：
4.1
通讯作者：
Pellegrini, Sandra
中科院分区：
文献类型：
--
作者：
Marijanovic, Zrinka;Ragimbeau, Josiane;Pellegrini, Sandra
I型IFN（干扰素）（IFN α/β）形成相关细胞因子家族，其通过与由IFNAR（IFN α受体亚基）1和2组成的受体结合来控制多种细胞功能。在I型IFN中，α 2和β亚型在它们与IFNAR 1的结合亲和力方面表现出很大的差异，并且表明高浓度的IFNAR 1可以补偿其对IFN α 2的低固有结合亲和力。我们通过研究几种细胞系中相对IFNAR 1/IFNAR 2表面水平与IFN α 2和IFN β信号转导效力之间的关系，测试了受体近端信号转导事件是否对IFNAR 1表面浓度敏感。为此，我们监测了JAK（Janus激酶）/STAT（信号转导和转录激活因子）蛋白的激活谱，测量了每个受体亚基的基础和配体诱导的表面衰减，并测试了IFNAR 1水平对IFNa 2信号传导效力的影响。我们的数据表明，细胞表面IFNAR 1水平确实是功能复合物组装的限制因素，但其浓度增加不会转化为IFN α/β差异JAK/STAT信号传导，也不会改变参与受体的动力学。然而，重要的是，我们的数据突出了IFNAR 2路由的差异效应。在IFN α 2结合后，IFNAR 2被内化，但不是像与IFN复合时那样被引导降解，而是返回细胞表面。这些观察结果强烈表明，稳定性和细胞内的三元复合物的寿命占IFNAR 2的差分控制。此外，本研究开辟了有吸引力的可能性，内体启动的信号可能有助于IFN α/β差异生物活性。
Type I IFNs (interferons) (IFN alpha/beta) form a family of related cytokines that control a variety of cellular functions through binding to a receptor composed of IFNAR (IFN alpha receptor subunit) 1 and 2. Among type I IFNs, the alpha 2 and beta subtypes exhibit a large difference in their binding affinities to IFNAR1, and it was suggested that high concentrations of IFNAR1 may compensate for its low intrinsic binding affinity for IFN alpha 2. We tested whether receptor-proximal signalling events are sensitive to IFNAR1 surface concentration by investigating the relationship between relative IFNAR1/IFNAR2 surface levels and IFN alpha 2 and IFN beta signalling potencies in several cell lines. For this, we monitored the activation profile of JAK (Janus kinase)/STAT (signal transducer and activator of transcription) proteins, measured basal and ligand-induced surface decay of each receptor subunit and tested the effect of variable IFNAR1 levels on IFNa2 signalling potency. Our data show that the cell-surface IFNAR1 level is indeed a limiting factor for assembly of the functional complex, but an increased concentration of it does not translate into an IFN alpha/beta differential JAK/STAT signalling nor does it change the dynamics of the engaged receptor. Importantly, however, our data highlight a differential effect upon routing of IFNAR2. Following binding of IFN alpha 2, IFNAR2 is internalized, but, instead of being routed towards degradation as it is when complexed to IFN, it recycles back to the cell surface. These observations suggest strongly that the stability and the intracellular lifetime of the ternary complex account for the differential control of IFNAR2. Moreover, the present study opens up the attractive possibility that endosomal-initiated signalling may contribute to IFN alpha/beta differential bioactivities.