Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, 26 rue d'Ulm, F-75248 Paris, France.
Institut National de la Santé et de la Recherche Médicale (INSERM) U1143, 75005 Paris, France.
Nat Commun. 2016 Dec 5;7:13476. doi: 10.1038/ncomms13476.
Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation. Depletion of VPS35 leads to abnormally prolonged residency and association of the IFNAR subunits at the early endosome, resulting in increased activation of STAT1- and IFN-dependent gene transcription. These experimental data establish the retromer complex as a key spatiotemporal regulator of IFNAR endosomal sorting and a new factor in type-I IFN-induced JAK/STAT signalling and gene transcription.
I 型干扰素（IFN）在抗病毒和细菌感染的免疫防御以及癌症免疫监视中发挥着关键作用。我们已经确定 I 型干扰素（IFN-α/β）受体（IFNAR）的网格蛋白依赖性内吞作用对于 JAK/STAT 信号转导是必需的。在这里，我们表明 IFNAR 复合物的内化 IFNAR1 和 IFNAR2 亚基在早期内涵体中被逆行转运体以不同的方式分拣。逆行转运体 VPS35 亚基与 IFNAR2 的结合导致 IFNAR2 回收至质膜，而 IFNAR1 则被分拣到溶酶体进行降解。VPS35 的耗竭导致 IFNAR 亚基在早期内涵体中异常延长的驻留和关联，从而导致 STAT1 和 IFN 依赖性基因转录的激活增加。这些实验数据确立了逆行转运体复合物作为 IFNAR 内涵体分拣的关键时空调节剂，以及 I 型 IFN 诱导的 JAK/STAT 信号转导和基因转录的新因素。
