法国PSL研究大学Christophe Lamaze和Cédric M. Blouin研究组合作揭示了STAM和Hrs依次与I型干扰素（IFN -α）受体相互作用，以控制JAK–STAT内体激活。2023年2月16日出版的《自然—细胞生物学》杂志发表了这一成果。

他们表明STAM与质膜上的IFN-α和-β受体（IFNAR）1和TYK2激酶的组成性关联阻止了I型IFNs的TYK2激活。IFN-α刺激的IFNAR内吞作用将STAM-IFNAR复合物递送到早期内体，在那里它与Hrs相互作用，从而减轻STAM对TYK2的抑制，并在内体触发IFNAR的信号传导。相反，当受到IFN-β的刺激时，IFNAR信号传导独立于Hrs发生，因为IFNAR被分选到一个不同的内体亚域。他们的结果确定了控制IFN-α时空激活IFNAR的分子机制，并确定了内体分选在IFN-α和IFN-β对JAK-STAT信号传导的差异调节中的核心作用。

研究人员表示，IFN激活JAK-STAT通路需要IFNAR的网格蛋白依赖性内吞作用，表明内体分选在此过程中的作用。在内体上选择性激活IFN-α/β诱导的JAK-STAT信号的分子机制仍然未知。

附：英文原文

Title: STAM and Hrs interact sequentially with IFN-α Receptor to control spatiotemporal JAK–STAT endosomal activation

Author: Zanin, Natacha, Viaris de Lesegno, Christine, Podkalicka, Joanna, Meyer, Thomas, Gonzalez Troncoso, Pamela, Bun, Philippe, Danglot, Lydia, Chmiest, Daniela, Urb, Sylvie, Piehler, Jacob, Blouin, Cdric M., Lamaze, Christophe

Issue&Volume: 2023-02-16

Abstract: Activation of the JAK–STAT pathway by type I interferons (IFNs) requires clathrin-dependent endocytosis of the IFN-α and -β receptor (IFNAR), indicating a role for endosomal sorting in this process. The molecular machinery that brings the selective activation of IFN-α/β-induced JAK–STAT signalling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and TYK2 kinase at the plasma membrane prevents TYK2 activation by type I IFNs. IFN-α-stimulated IFNAR endocytosis delivers the STAM–IFNAR complex to early endosomes where it interacts with Hrs, thereby relieving TYK2 inhibition by STAM and triggering signalling of IFNAR at the endosome. In contrast, when stimulated by IFN-β, IFNAR signalling occurs independently of Hrs as IFNAR is sorted to a distinct endosomal subdomain. Our results identify the molecular machinery that controls the spatiotemporal activation of IFNAR by IFN-α and establish the central role of endosomal sorting in the differential regulation of JAK–STAT signalling by IFN-α and IFN-β.

DOI: 10.1038/s41556-022-01085-6

Source: https://www.nature.com/articles/s41556-022-01085-6