Signaling from the RNA sensor RIG-I is regulated by ufmylation.
Signaling from the RNA sensor RIG-I is regulated by ufmylation.
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DOI：
10.1073/pnas.2119531119
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发表时间：
2022-04-12
影响因子：
11.1
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中科院分区：
文献类型：
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病毒RNA传感器RIG-I通过激活诱导干扰素的信号级联启动抗病毒先天免疫反应。RIG-I信号通路的激活受到高度调节，以快速建立保护性免疫反应，同时防止可能导致过度炎症或自身免疫性疾病的失调。在这里，我们描述了一种这样的调节机制。我们描述了UFL1，一个泛素样修饰物缀合系统称为泛素化的E3连接酶，对促进rig - 1信号传导很重要。利用分子方法，我们发现ufmyation促进rig - 1与膜靶向蛋白14-3-3ε的相互作用。因此，在RNA病毒感染的反应中，ufmyation积极调节RIG-I向其信号转导蛋白MAVS的募集，以诱导干扰素。rna结合蛋白RIG-I是抗病毒先天免疫反应的关键启动物。介导rig - 1下游抗病毒反应的信号通过接头蛋白MAVS转导，导致I型和III型干扰素（ifn）的诱导。这种信号转导发生在内质网(ER) -线粒体接触位点，rig - 1和其他信号蛋白在激活后被募集到这些位点。RIG-I信号被高度调控，以防止该途径的异常激活和IFN的失调诱导。在此之前，我们确定了UFL1，即泛素样修饰物偶联系统（称为ufmylation）的E3连接酶，作为响应rig - 1激活而招募到膜上er -线粒体接触位点的蛋白质之一。在这里，我们发现UFL1，以及ufmyation过程，促进IFN诱导，以响应RIG-I激活。我们发现，在RNA病毒感染后，UFL1被招募到膜靶向蛋白14-3-3ε上，然后该复合体被招募到激活RIG-I上，以促进下游先天免疫信号传导。重要的是，我们发现14-3-3ε在RIG-I激活后UFM1共轭增加。此外，细胞甲基化的缺失阻止了14-3-3ε与RIG-I的相互作用，从而取消了RIG-I与MAVS的相互作用，从而取消了诱导IFN的下游信号转导。我们的研究结果将ufmyation定义为RIG-I信号通路的一个完整的调控组成部分，并作为IFN诱导的翻译后控制。
The viral RNA sensor RIG-I initiates the antiviral innate immune response by activating a signaling cascade that induces interferon. Activation of the RIG-I signaling pathway is highly regulated to quickly mount a protective immune response while preventing dysregulation that can lead to excessive inflammation or autoimmune disorders. Here, we characterize one such mechanism of regulation. We describe that UFL1, an E3 ligase for the ubiquitin-like modifier conjugation system called ufmylation, is important to promote RIG-I signaling. Using molecular approaches, we show that ufmylation promotes RIG-I interaction with the membrane-targeting protein 14-3-3ε. As such, ufmylation positively regulates RIG-I recruitment to its signaling adaptor protein MAVS for induction of interferon in response to RNA virus infection. The RNA-binding protein RIG-I is a key initiator of the antiviral innate immune response. The signaling that mediates the antiviral response downstream of RIG-I is transduced through the adaptor protein MAVS and results in the induction of type I and III interferons (IFNs). This signal transduction occurs at endoplasmic reticulum (ER)–mitochondrial contact sites, to which RIG-I and other signaling proteins are recruited following their activation. RIG-I signaling is highly regulated to prevent aberrant activation of this pathway and dysregulated induction of IFN. Previously, we identified UFL1, the E3 ligase of the ubiquitin-like modifier conjugation system called ufmylation, as one of the proteins recruited to membranes at ER–mitochondrial contact sites in response to RIG-I activation. Here, we show that UFL1, as well as the process of ufmylation, promote IFN induction in response to RIG-I activation. We found that following RNA virus infection, UFL1 is recruited to the membrane-targeting protein 14–3-3ε and that this complex is then recruited to activated RIG-I to promote downstream innate immune signaling. Importantly, we found that 14–3-3ε has an increase in UFM1 conjugation following RIG-I activation. Additionally, loss of cellular ufmylation prevents the interaction of 14–3-3ε with RIG-I, which abrogates the interaction of RIG-I with MAVS and thus the downstream signal transduction that induces IFN. Our results define ufmylation as an integral regulatory component of the RIG-I signaling pathway and as a posttranslational control for IFN induction.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
6
作者：
Daniel J;Liebau E
通讯作者：
Liebau E
影响因子：
3.7
作者：
Horner SM;Wilkins C;Badil S;Iskarpatyoti J;Gale M Jr
通讯作者：
Gale M Jr
影响因子：
4.8
作者：
Beachboard, Dia C.;Park, Moonhee;Horner, Stacy M.
通讯作者：
Horner, Stacy M.
影响因子：
11.4
作者：
Komatsu, M;Chiba, T;Tanaka, K
通讯作者：
Tanaka, K