The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation.
The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation.
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DOI：
10.1371/journal.ppat.1000650
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发表时间：
2009-11
期刊：
影响因子：
6.7
通讯作者：
Hiscott J
中科院分区：
文献类型：
--
作者：
Nakhaei P;Mesplede T;Solis M;Sun Q;Zhao T;Yang L;Chuang TH;Ware CF;Lin R;Hiscott J
先天免疫反应的主要作用是限制感染性病原体的传播，激活Toll样受体(TLR)和Rig样受体(RLR)通路，导致抗炎反应。限制这些信号通路的激活对于防止宿主的组织损伤同样至关重要。Triad3A是一种E3泛素连接酶，它与TLR信号的几个成分相互作用，调节TLR的活性。在本研究中，我们证明了Triad3A通过Lys48连接的泛素介导的肿瘤坏死因子受体相关因子3(TRAF3)适配器的降解来负向调节RIG-I RNA传感途径。Triad3A在dsRNA暴露或病毒感染后被诱导，并以剂量依赖的方式降低TRAF3水平；此外，Triad3A的表达通过Ser-396磷酸化而阻断IRF-3的激活，并抑制1型干扰素和抗病毒基因的表达。Lys48连接的Triad3A泛素化TRAF3增加了TRAF3的周转，而稳定的shRNA表达降低了Triad3A的表达，这与VSV或仙台病毒感染后TRAF3蛋白表达的增加和抗病毒应答的增强有关。Triad3A和TRAF3在物理上相互作用，TRAF3残基Y440和Q442-以前被证明对MAVS适配器的结合是重要的-也是Triad3A的关键。Triad3A的TRAF相互作用基序(TIM)的点突变使其与TRAF3相互作用并调节RIG-I信号的能力丧失。TRAF3似乎在病毒感染后经历了顺序的泛素“免疫编辑”，这对于调节依赖RIG-I的抗病毒反应信号至关重要。因此，Triad3A代表一种多功能的E3泛素连接酶，它通过靶向TRAF3在RNA病毒感染后降解来负面调节RIG样受体信号。RNA病毒感染是通过TLR依赖和TLR非依赖机制来检测的。早期病毒复制中间产物由两个新近确定的囊状病毒RNA受体RIG-I和MDA-5检测，导致促炎细胞因子和I型干扰素(IFN)的产生。功能失调的反应，无论是无反应或高反应，都可能导致急性和慢性免疫缺陷和炎症性疾病。因此，必须严格控制RLR信令的强度和持续时间。调节先天免疫受体及其下游适配器的一个一般机制涉及泛素化途径介导的蛋白质降解。我们的研究表明，E3泛素连接酶Triad3A通过靶向适配分子TRAF3，通过Lys48连接的泛素介导的降解来负性调节RIG-I样受体途径。因此，Triad3A是参与RNA病毒感染引发的宿主抗病毒反应的负调控的关键分子。
The primary role of the innate immune response is to limit the spread of infectious pathogens, with activation of Toll-like receptor (TLR) and RIG-like receptor (RLR) pathways resulting in a pro-inflammatory response required to combat infection. Limiting the activation of these signaling pathways is likewise essential to prevent tissue injury in the host. Triad3A is an E3 ubiquitin ligase that interacts with several components of TLR signaling and modulates TLR activity. In the present study, we demonstrate that Triad3A negatively regulates the RIG-I RNA sensing pathway through Lys48-linked, ubiquitin-mediated degradation of the tumor necrosis factor receptor-associated factor 3 (TRAF3) adapter. Triad3A was induced following dsRNA exposure or virus infection and decreased TRAF3 levels in a dose-dependent manner; moreover, Triad3A expression blocked IRF-3 activation by Ser-396 phosphorylation and inhibited the expression of type 1 interferon and antiviral genes. Lys48-linked ubiquitination of TRAF3 by Triad3A increased TRAF3 turnover, whereas reduction of Triad3A expression by stable shRNA expression correlated with an increase in TRAF3 protein expression and enhancement of the antiviral response following VSV or Sendai virus infection. Triad3A and TRAF3 physically interacted together, and TRAF3 residues Y440 and Q442—previously shown to be important for association with the MAVS adapter—were also critical for Triad3A. Point mutation of the TRAF-Interacting-Motif (TIM) of Triad3A abrogated its ability to interact with TRAF3 and modulate RIG-I signaling. TRAF3 appears to undergo sequential ubiquitin “immuno-editing” following virus infection that is crucial for regulation of RIG-I-dependent signaling to the antiviral response. Thus, Triad3A represents a versatile E3 ubiquitin ligase that negatively regulates RIG-like receptor signaling by targeting TRAF3 for degradation following RNA virus infection. RNA virus infection is detected through TLR-dependent and TLR-independent mechanisms. Early viral replicative intermediates are detected by two recently characterized cystolic viral RNA receptors, RIG-I and MDA-5, leading to the production of pro-inflammatory cytokines and type I interferons (IFNs). Dysfunctional responses, either failure to respond or hyper-responsiveness, may lead to both acute and chronic immunodeficiency and inflammatory diseases. Thus, the intensity and duration of RLR signaling must be tightly controlled. One general mechanism by which innate immune receptors and their downstream adapters are regulated involves protein degradation mediated by the ubiquitination pathway. Our study demonstrates that the E3 ubiquitin ligase Triad3A negatively regulates the RIG-I-like receptor pathway by targeting the adapter molecule TRAF3 for proteasomal degradation through Lys48-linked ubiquitin-mediated degradation. Thus, Triad3A represents a key molecule involved in the negative regulation of the host antiviral response triggered by RNA virus infection.
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