Department of Immunology, School of Medicine, UConn Health, Farmington, CT.
Department of Microbiology & Immunology, School of Medicine, New York Medical College, Valhalla, NY; and.
J Immunol. 2021 Jun 1;206(11):2682-2691. doi: 10.4049/jimmunol.1901337. Epub 2021 May 21.
Type I/III IFNs induce expression of hundreds of IFN-stimulated genes through the JAK/STAT pathway to combat viral infections. Although JAK/STAT signaling is seemingly straightforward, it is nevertheless subjected to complex cellular regulation. In this study, we show that an ubiquitination regulatory X (UBX) domain-containing protein, UBXN6, positively regulates JAK-STAT1/2 signaling. Overexpression of UBXN6 enhanced type I/III IFNs-induced expression of IFN-stimulated genes, whereas deletion of UBXN6 inhibited their expression. RNA viral replication was increased in human UBXN6-deficient cells, accompanied by a reduction in both type I/III IFN expression, when compared with UBXN6-sufficient cells. Mechanistically, UBXN6 interacted with tyrosine kinase 2 (TYK2) and inhibited IFN-β-induced degradation of both TYK2 and type I IFNR. These results suggest that UBXN6 maintains normal JAK-STAT1/2 signaling by stabilizing key signaling components during viral infection.
I 型/III 型干扰素通过 JAK/STAT 途径诱导数百种干扰素刺激基因的表达，以抵抗病毒感染。尽管 JAK/STAT 信号通路看似简单，但它仍然受到复杂的细胞调控。在这项研究中，我们发现一个含有泛素化调节 X（UBX）结构域的蛋白质 UBXN6 正向调节 JAK-STAT1/2 信号通路。UBXN6 的过表达增强了 I 型/III 型干扰素诱导的干扰素刺激基因的表达，而 UBXN6 的缺失则抑制了其表达。与 UBXN6 充分表达的细胞相比，人 UBXN6 缺陷细胞中的 RNA 病毒复制增加，同时 I 型/III 型干扰素的表达也减少。在机制上，UBXN6 与酪氨酸激酶 2（TYK2）相互作用，并抑制 IFN-β诱导的 TYK2 和 I 型干扰素受体的降解。这些结果表明，UBXN6 通过在病毒感染过程中稳定关键信号成分，维持正常的 JAK-STAT1/2 信号通路。
