Institute of Hansen's Disease, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Institute of Hansen's Disease, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2020 Feb 19;522(4):939-944. doi: 10.1016/j.bbrc.2019.11.189. Epub 2019 Dec 2.
The retinoic-acid inducible gene (RIG)-I is a cytoplasmic pattern recognition receptor that senses single-stranded (ss) or double-stranded (ds) RNA. RIG-I also senses AT-rich dsDNA, poly(dA:dT), through the action of an RNA polymerase III-transcribed RNA intermediate. Upon the binding of an RNA ligand, RIG-I binds to the mitochondrial antiviral-signaling protein (MAVS) and induces the formation of filamentous aggregates of MAVS, leading to the formation of a signaling complex that drives Type I interferon (IFN) responses. In the current study, we investigated the issue of whether the SUMOylation of MAVS induced by poly(dA:dT) affects the aggregation of MAVS in the RIG-I/MAVS pathway in human keratinocytes. Our results show that the poly(dA:dT)-induced secretion of IFN-β was dependent on RIG-I and MAVS. The inhibition of SUMOylation by Ginkgolic acid or Ubc9 siRNA was found to inhibit the poly(dA:dT)-induced secretion of IFN-β, suggesting that the SUMOylation is required for the poly(dA:dT)-activated RIG-I/MAVS pathway, which drives the secretion of IFN-β. In addition, treatment with poly(dA:dT) enhanced the formation of polymeric chains of small-ubiquitin like modifiers (SUMO)3, but not SUMO1 and SUMO2, on MAVS. Our results also show that the conjugation of SUMO3 to MAVS induced by poly (dA:dT) enhanced the aggregation of MAVS. These collective results show that the formation of SUMO3-conjugated chains of MAVS induced by poly (dA:dT), a ligand of RIG-I, enhances the aggregation of MAVS which, in turn, drives the secretion of IFN-β in human keratinocytes.
视黄酸诱导基因（RIG）-I 是一种细胞质模式识别受体，可识别单链（ss）或双链（ds）RNA。RIG-I 还通过 RNA 聚合酶 III 转录的 RNA 中间产物识别富含 AT 的 dsDNA、聚（dA：dT）。在结合 RNA 配体后，RIG-I 与线粒体抗病毒信号蛋白（MAVS）结合，并诱导 MAVS 形成丝状聚集物，形成一个信号复合物，从而驱动 I 型干扰素（IFN）反应。在本研究中，我们研究了聚（dA：dT）诱导的 MAVS 泛素化是否影响 RIG-I/MAVS 途径中 MAVS 的聚集。我们的结果表明，聚（dA：dT）诱导的 IFN-β 分泌依赖于 RIG-I 和 MAVS。通过 Ginkgolic 酸或 Ubc9 siRNA 抑制 SUMO 化发现，聚（dA：dT）诱导的 IFN-β 分泌受到抑制，表明 SUMO 化是聚（dA：dT）激活的 RIG-I/MAVS 途径所必需的，该途径驱动 IFN-β 的分泌。此外，用聚（dA：dT）处理可增强 MAVS 上小泛素样修饰物（SUMO）3 的聚合链的形成，但不增强 SUMO1 和 SUMO2 的形成。我们的结果还表明，聚（dA：dT）诱导的 SUMO3 与 MAVS 的结合增强了 MAVS 的聚集。这些结果表明，RIG-I 配体聚（dA：dT）诱导的 MAVS 上 SUMO3 缀合链的形成增强了 MAVS 的聚集，进而驱动人角质形成细胞中 IFN-β 的分泌。
