The NLRP4-DTX4 axis: a key suppressor of TBK1 and innate antiviral signaling.
The NLRP4-DTX4 axis: a key suppressor of TBK1 and innate antiviral signaling.
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DOI：
10.1038/cmi.2012.49
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发表时间：
2012-11
影响因子：
24.1
通讯作者：
中科院分区：
文献类型：
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先天免疫系统提供了第一道防线，以保护免受病原性细菌或病毒。宿主通过经由生殖系编码的模式识别受体（包括Toll样受体、RIG-I样受体（RLR）、NOD样受体（NLR）和DNA传感器）识别病原体相关的分子模式来“感知”病原体感染。在受体接合时，信号级联事件最终导致限制病毒复制的I型干扰素（IFN）IFN-α和IFN-b的产生。RIG-I和MDA 5是识别病毒基因组RNA并将下游信号传递到线粒体衔接分子MAVS（也称为IPS-1、VISA或Cardif）的关键RLR。1 MAVS使锚定至线粒体的信号传导复合物成核，所述信号传导复合物含有E3泛素连接酶TRAF 3、非经典IkB激酶（IKK）TBK 1和IKKi（也称为IKK γ）以及衔接子分子NEMO（也称为IKK γ）和TANK。1 TBK 1和IKKi磷酸化干扰素调节因子3（IRF 3）转录因子以触发IRF 3二聚化和核定位以激活I型IFN转录。2 TBK 1和IKKi均受病毒感染期间发生的翻译后修饰的调节，包括TRAF 3或其他E3泛素连接酶引起的赖氨酸63（K63）连接的多聚泛素化。3，4 TBK 1/IKKi K63连接的多聚泛素化与它们的活化有关，并可能参与募集含有泛素结合结构域的信号复合物以传递下游信号。I型IFN信号传导的失调，其特征在于IFN-a和IFN-b的过度产生，已经涉及许多自身免疫性疾病，如系统性红斑狼疮。因此，IFN的产生受到许多机制的严格调节控制，以维持免疫稳态。在Nature Immunology最近的一篇文章中，Cui等人6报道了NLR蛋白NLRP 4通过靶向TBK 1进行蛋白酶体降解，在RLR途径中作为负调节剂发挥作用。NLR代表一个天然免疫调节蛋白家族，其由核苷酸结合和寡聚化（NOD）结构域、富含亮氨酸的重复区和可变氨基末端效应结构域组成。NLR可以作为RLR信号通路的激活剂或负调节剂发挥作用。7 NLR家族成员NLRP 4已被报道抑制核因子-kB信号通路;然而，其在RLR通路中的作用先前未被研究。8作者最初使用编码各种NLR的载体进行过表达筛选，并将NLRP 4鉴定为RLR信号传导的抑制剂。6 NLRP 4抑制poly（I：C）（双链RNA模拟物）、poly（dA：dT）（双链DNA模拟物）和水泡性口炎病毒-GFP感染对IFN-b和ISRE荧光素酶报告基因的诱导。通过RNA干扰敲低NLRP 4增强了293 T细胞中IFN-b和ISRE荧光素酶报告基因的激活。此外，作者使用了更多生理相关的免疫细胞，包括单核细胞THP-1细胞和外周血单核细胞，以证明NLRP 4的敲低增强了病毒感染期间产生的干扰素刺激基因的表达。为了鉴定NLRP 4的靶点，作者过表达了RLR/Toll样受体途径中的关键信号分子用NLRP 4（RIGI、MDA 5、MAVS、TRIF、TBK 1和IKKi）激活IFN-b和ISRE荧光素酶报告基因，发现NLRP 4抑制除IKKi以外的所有表达载体的激活。因此，NLRP 4在下游步骤抑制RLR信号传导，可能在TBK 1水平。确实...
The innate immune system provides the first line of defense for protection against pathogenic bacteria or viruses. The host ‘senses’ pathogen infection by recognition of pathogen-associated molecular patterns via germ-line-encoded patternrecognition receptors including Toll-like receptors, RIG-I-like receptors (RLRs), NOD-like receptors (NLRs) and DNA sensors. Upon receptor engagement, signaling cascade events culminate in the production of the type I interferons (IFNs) IFN-a and IFN-b that restrict virus replication. RIG-I and MDA5 are the key RLRs that recognize viral genomic RNAs and transmit downstream signals to the mitochondrial adaptor molecule MAVS (also known as IPS-1, VISA or Cardif). 1 MAVS nucleates a signaling complex anchored to the mitochondria containing the E3 ubiquitin ligase TRAF3, the non-canonical IkB kinases (IKKs) TBK1 and IKKi (also known as IKK epsilon) and the adaptor molecules NEMO (also known as IKK gamma) and TANK. 1 TBK1 and IKKi phosphorylate the interferon regulatory factor 3 (IRF3) transcription factor to trigger IRF3 dimerization and nuclear localization to activate type I IFN transcription. 2 TBK1 and IKKi are both regulated by posttranslational modifications that occur during virus infection including lysine 63 (K63)-linked polyubiquitination by TRAF3 or other E3 ubiquitin ligases. 3, 4 TBK1/IKKi K63-linked polyubiquitination is linked to their activation and may be involved in recruiting signaling complexes containing ubiquitin-binding domains to transmit downstream signals. Dysregulation of type I IFN signaling, characterized by overproduction of IFN-a and IFN-b, has been implicated in numerous autoimmune diseases such as systemic lupus erythematosus. 5 Therefore, the production of IFN is subject to tight regulatory control by numerous mechanisms to maintain immune homeostasis. In a recent article in Nature Immunology, Cui et al. 6 have reported that the NLR protein NLRP4 functions as a negative regulator in the RLR pathway by targeting TBK1 for proteasomal degradation. NLRs represent a family of innate immune regulatory proteins that consist of a nucleotidebinding and oligomerization (NOD) domain, a leucine-rich repeat region and a variable amino-terminal effector domain. NLRs may function as either activators or negative regulators of the RLR signaling pathway. 7 NLRP4, an NLR family member, has been reported to inhibit the nuclear factor-kB signaling pathway; however, its role in the RLR pathway was not previously examined. 8 The authors initially performed an overexpression screen using vectors encoding various NLRs and identified NLRP4 as an inhibitor of RLR signaling. 6 NLRP4 inhibited the induction of IFN-b and ISRE luciferase reporters by poly (I: C)(doublestranded RNA mimic), poly (dA: dT)(doublestranded DNA mimic) and vesicular stomatitis virus-GFP infection. Knockdown of NLRP4 by RNA interference potentiated the activation of IFN-b and ISRE luciferase reporters in 293T cells. Furthermore, the authors used more physiologically relevant immune cells including monocytic THP-1 cells and peripheral blood mononuclear cells to demonstrate that knockdown of NLRP4 enhanced the expression of interferon stimulated genes generated during virus infection.To identify the target (s) of NLRP4, the authors overexpressed key signaling molecules in the RLR/Toll-like receptor pathways (RIGI, MDA5, MAVS, TRIF, TBK1 and IKKi) to activate IFN-b and ISRE luciferase reporters and found that NLRP4 inhibited activation by all of the expression vectors except for IKKi. 6 Therefore, NLRP4 inhibited RLR signaling at a downstream step, likely at the level of TBK1. Indeed …
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DOI：
10.1084/jem.20120024
发表时间：
2012-09-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Zhang M;Wang L;Zhao X;Zhao K;Meng H;Zhao W;Gao C
通讯作者：
Gao C
影响因子：
7.7
作者：
Friedman, Constantin S.;O'Donnell, Marie Anne;Ting, Adrian T.
通讯作者：
Ting, Adrian T.
NLRP4 通过泛素连接酶 DTX4 靶向激酶 TBK1 进行降解，从而负调节 I 型干扰素信号传导
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
Wertz, IE;O'Rourke, KM;Dixit, VM
通讯作者：
Dixit, VM
影响因子：
56.9
作者：
Sharma, S;tenOever, BR;Hiscott, J
通讯作者：
Hiscott, J