Tremblay Nicolas, Baril Martin, Chatel-Chaix Laurent, Es-Saad Salwa, Park Alex Young, Koenekoop Robert K, Lamarre Daniel
Centre de Recherche du CHUM (CRCHUM), Montréal, Québec, Canada.
Faculté de Médecine, Université de Montréal, Montréal, Canada.
PLoS Pathog. 2016 Jul 25;12(7):e1005772. doi: 10.1371/journal.ppat.1005772. eCollection 2016 Jul.
Spliceosomal SNRNP200 is a Ski2-like RNA helicase that is associated with retinitis pigmentosa 33 (RP33). Here we found that SNRNP200 promotes viral RNA sensing and IRF3 activation through the ability of its amino-terminal Sec63 domain (Sec63-1) to bind RNA and to interact with TBK1. We show that SNRNP200 relocalizes into TBK1-containing cytoplasmic structures upon infection, in contrast to the RP33-associated S1087L mutant, which is also unable to rescue antiviral response of SNRNP200 knockdown cells. This functional rescue correlates with the Sec63-1-mediated binding of viral RNA. The hindered IFN-β production of knockdown cells was further confirmed in peripheral blood cells of RP33 patients bearing missense mutation in SNRNP200 upon infection with Sendai virus (SeV). This work identifies a novel immunoregulatory role of the spliceosomal SNRNP200 helicase as an RNA sensor and TBK1 adaptor for the activation of IRF3-mediated antiviral innate response.
剪接体SNRNP200是一种Ski2样RNA解旋酶，与色素性视网膜炎33（RP33）相关。我们发现，SNRNP200通过其氨基末端Sec63结构域（Sec63-1）结合RNA并与TBK1相互作用的能力，促进病毒RNA感应和IRF3激活。我们发现，与RP33相关的S1087L突变体不同，SNRNP200在感染后重新定位到含有TBK1的细胞质结构中，而S1087L突变体也无法挽救SNRNP200敲低细胞的抗病毒反应。这种功能挽救与Sec63-1介导的病毒RNA结合相关。在用仙台病毒（SeV）感染后，携带SNRNP200错义突变的RP33患者外周血细胞中，敲低细胞中受阻的IFN-β产生得到进一步证实。这项研究确定了剪接体SNRNP200解旋酶作为RNA传感器和TBK1衔接蛋白在激活IRF3介导的抗病毒固有反应中的新免疫调节作用。
