Autophagy takes the STING out of DNA sensing.
Autophagy takes the STING out of DNA sensing.
复制标题
自噬将STING从DNA传感中移除。
DOI：
10.1038/s41423-021-00797-3
复制
发表时间：
2022-01
影响因子：
24.1
通讯作者：
Maluquer de Motes C
中科院分区：
文献类型：
--
作者：
Maluquer de Motes C
先天免疫系统已经进化到可以检测与入侵微生物相关的分子特征以及这些微生物引起的细胞损伤。识别微生物基因组，特别是细胞内微生物（如病毒）的基因组，对于触发保护性反应和预防感染至关重要。许多核酸形式与病原体（例如，5Lppp-RNA，dsRNA）独特相关，或在感染期间定位于异常细胞区室（例如，胞质DNA），促进自我和非自我之间的区别[1]。特别地，细胞溶质DNA的检测已经成为感染以及癌症、无菌性炎症和自身免疫性疾病（如系统性红斑狼疮（SLE））中的重要过程，其中自身DNA诱导I型干扰素（IFN）信号传导并增加IFN刺激基因（ISG）的表达。尽管几十年来人们已经知道外源DNA会激活有效的免疫反应[2]，但直到最近我们才开始确定负责这些反应的蛋白质及其工作方式[3]。在这个过程中的一个关键分子是干扰素基因刺激因子（STING），一种识别环GMP-AMP（cGAMP）的ER/Golgi驻留蛋白，该环GMP-AMP是激活的DNA结合酶cGAMP合酶（cGAS）的产物。STING的激活导致涉及IFN和多种炎性基因的有效转录应答。为了确保免疫应答是成比例的，并且可以消除外源性挑战而不诱导过度的免疫病理学，必须保持激活和失活之间的良好平衡[4]。在细胞和分子免疫学，侯等人。[5]的文件。揭示了活化的STING如何被自噬货物受体CCDC 50递送降解，阐明了控制STING周转和调节对感染和慢性自身免疫性疾病的免疫应答的机制（图1）。自噬是介导不需要的货物和细胞器的分解和再循环的重要过程。自噬是许多细胞应激反应的组成部分，包括感染和炎症期间诱导的那些。自噬调节免疫和炎症反应的诱导和抑制，这种复杂的关系可能由与底物选择性识别相关的机制决定。细胞货物通常通过自噬衔接子如p62、NBR 1或NDP 52导向自噬体。这些衔接子通过泛素结合结构域（UBD）识别多泛素化底物，并通过与膜蛋白LC 3（ATG 8）的结合将这些底物靶向新生的吞噬细胞。CCDC 50（也称为Ymer）与这些适配器有相似之处。CCDC 50含有识别多聚泛素化底物和LC 3相互作用的UBD
The innate immune system has evolved to detect molecular signatures associated with invading microbes and the cellular damage these microbes cause. Recognition of microbial genomes, particularly those of intracellular microbes such as viruses, is crucial in triggering a protective response and preventing infection. Many nucleic acid forms are uniquely associated with pathogens (eg, 5Lppp-RNA, dsRNA) or localize in abnormal cellular compartments during infection (eg, cytosolic DNA), facilitating the distinction between self and nonself [1]. In particular, the detection of cytosolic DNA has emerged as an important process in infection, as well as cancer, sterile inflammation, and autoimmune diseases such as systemic lupus erythematosus (SLE), in which self-DNA induces type I interferon (IFN) signaling and increases the expression of IFN-stimulated genes (ISGs). Although it has been known for decades that foreign DNA activates potent immune responses [2], only recently have we started to identify the proteins that are responsible for these responses and how they work [3]. A crucial molecule in this process is stimulator of interferon genes (STING), an ER/Golgiresident protein that recognizes cyclic GMP-AMP (cGAMP), the product of the activated DNA-binding enzyme cGAMP synthase (cGAS). Activation of STING results in a potent transcriptional response involving IFN and multiple inflammatory genes. To ensure that immune responses are proportionate and can eliminate the exogenous challenge without inducing excessive immunopathology, a fine balance between activation and deactivation must be maintained [4]. Writing in Cellular & Molecular Immunology, Hou et al.[5]. revealed how activated STING is delivered for degradation by the autophagic cargo receptor CCDC50, illuminating the mechanisms that control STING turnover and regulate immune responses to infection and chronic autoimmune disease (Fig. 1).Autophagy is an essential process that mediates the breakdown and recycling of unwanted cargo and cellular organelles. Autophagy is an integral part of many cellular stress responses, including those induced during infection and inflammation. Autophagy modulates both the induction and suppression of immune and inflammatory responses, and this complex relationship is likely to be determined by mechanisms associated with the selective recognition of substrates. Cellular cargo is typically directed to autophagosomes by autophagy adaptors such as p62, NBR1, or NDP52. These adaptors recognize polyubiquitylated substrates via ubiquitin-binding domains (UBDs) and target these substrates to nascent phagophores via association with the membrane protein LC3 (ATG8). CCDC50 (also known as Ymer) shares similarities with these adaptors. CCDC50 contains a UBD that recognizes polyubiquitylated substrates and LC3-interacting
登录
查看更多内容
自噬受体 CCDC50 调节病毒感染和自身免疫性疾病中 STING 介导的干扰素反应
影响因子：
24.1
作者：
Hou, Panpan;Lin, Yuxin;Guo, Deyin
通讯作者：
Guo, Deyin
影响因子：
64.8
作者：
ROTEM, Z;COX, RA;ISAACS, A
通讯作者：
ISAACS, A
影响因子：
8.8
作者：
Xia T;Konno H;Ahn J;Barber GN
通讯作者：
Barber GN
影响因子：
64.5
作者：
Marshall, Richard S.;Hua, Zhihua;Vierstra, Richard D.
通讯作者：
Vierstra, Richard D.
影响因子：
7
作者：
Postal M;Vivaldo JF;Fernandez-Ruiz R;Paredes JL;Appenzeller S;Niewold TB
通讯作者：
Niewold TB