鸟苷酸结合蛋白家族在感染性疾病中调控炎症小体活化的研究进展

doi:10.16288/j.yczz.23-119

遗传 ›› 2023, Vol. 45 ›› Issue (11): 1007-1017.doi: 10.16288/j.yczz.23-119

鸟苷酸结合蛋白家族在感染性疾病中调控炎症小体活化的研究进展

全舒婷¹(), 焦伟伟^1,²(), 徐放^3,², 孙琳^1,², 綦辉^1,²(), 申阿东^1,²()

1.国家儿童医学中心，首都医科大学附属北京儿童医院，北京市儿科研究所，国家呼吸系统疾病临床医学研究中心，儿科学国家重点学科，儿科重大疾病研究教育部重点实验室，儿童呼吸道感染性疾病研究北京市重点实验室，北京 100045
2.首都医科大学附属北京儿童医院保定医院，保定市儿童感染性疾病精准诊治重点实验室，保定 071000
3.国家儿童医学中心，首都医科大学附属北京儿童医院，北京市儿科研究所，儿科学国家重点学科，儿科重大疾病研究教育部重点实验室，出生缺陷遗传学研究北京市重点实验室，遗传与出生缺陷防治中心，北京 100045

收稿日期:2023-06-15 修回日期:2023-08-22 出版日期:2023-11-20 发布日期:2023-09-14
通讯作者: 綦辉,申阿东 E-mail:qst137@163.com;jiaowei310@163.com;qh20021983@163.com;shenad16@hotmail.com
作者简介:全舒婷，博士研究生，专业方向：儿内科。E-mail: qst137@163.com;|焦伟伟，博士，研究员，研究方向：呼吸感染疾病病原研究。E-mail: jiaowei310@163.com;
全舒婷和焦伟伟并列第一作者。
基金资助:
国家自然科学基金项目(81871617);国家自然科学基金项目(81701971);国家自然科学基金项目(82172280);国家自然科学基金项目(82100010);中国科学院病原微生物与免疫学重点实验室开放课题(CASPMI202201);保定市科技计划(2272P012);北京市卫生健康委员会高层次公共卫生技术人才培养计划(2022-3-041)

Advances in the regulation of inflammasome activation by GBP family in infectious diseases

Shuting Quan¹(), Weiwei Jiao^1,²(), Fang Xu^3,², Lin Sun^1,², Hui Qi^1,²(), Adong Shen^1,²()

1. Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, MOE Key Laboratory of Major Diseases in Children, National Key Discipline of Pediatrics, National Clinical Research Center for Respiratory Diseases, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
2. Baoding Key Laboratory for Precision Diagnosis and Treatment of Infectious Diseases in Children, Baoding Hospital of Beijing Children’s Hospital, Capital Medical University, Baoding 071000, China
3. Genetics and Birth Defects Control Center, Beijing Key Laboratory for Genetics of Birth Defects, MOE Key Laboratory of Major Diseases in Children, National Key Discipline of Pediatrics, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China

Received:2023-06-15 Revised:2023-08-22 Published:2023-11-20 Online:2023-09-14
Contact: Hui Qi,Adong Shen E-mail:qst137@163.com;jiaowei310@163.com;qh20021983@163.com;shenad16@hotmail.com
Supported by:
National Natural Science Foundation of China(81871617);National Natural Science Foundation of China(81701971);National Natural Science Foundation of China(82172280);National Natural Science Foundation of China(82100010);CAS Key Laboratory of Pathogenic Microbiology and Immunology Open Project(CASPMI202201);Baoding Science and Technology Plan(2272P012);Training Plan for High-Level Public Health Technical Talents of Beijing Municipal Health Commission(2022-3-041)

摘要/Abstract

摘要：

鸟苷酸结合蛋白(guanylate-binding proteins，GBP)是一类干扰素诱导蛋白，在应对细菌、病毒、衣原体以及寄生虫等病原体感染时，其发挥的作用存在差异，并且影响感染性疾病的发展和结局。目前，研究者发现在细菌等病原体感染引发的细胞自主免疫中，GBP蛋白通过影响炎症小体的经典和非经典活化途径调控细胞焦亡。本文对GBP家族成员结构、进化特征以及炎症小体的经典和非经典活化途径进行了介绍，综述了GBP蛋白调控炎症小体活化的相关研究进展，归纳总结了GBP蛋白影响不同病原体感染的作用机制，以期为感染性疾病的发病机制和诊疗提供新的基础研究线索。

关键词: 鸟苷酸结合蛋白, 感染性疾病, 炎症小体, 炎症小体经典活化途径

Abstract:

Guanylate-binding proteins (GBPs) are a subfamily of interferon-inducible proteins that undertake distinct roles in the the context of bacteria, virus, chlamydia and parasites infections. These proteins exert a notable influence on the progression and outcomes of infectious diseases. Within the realm of host cell-autonomous immunity against pathogens, GBPs have been identified as the regulators of pyroptosis through canonical and noncanonical inflammasome activation pathways. In this review, we summarize the structure and evolution of GBP family members, the canonical and noncanonical inflammasome activation pathways, the roles of GBPs in regulating inflammasome activation, and the mechanisms of GBPs affecting infections induced by different pathogens. We hope to provide new basic research clues for the pathogenesis and diagnosis and treatment of infectious diseases.

Key words: guanylate-binding proteins, infectious disease, inflammasome, canonical inflammasome activation

全舒婷, 焦伟伟, 徐放, 孙琳, 綦辉, 申阿东. 鸟苷酸结合蛋白家族在感染性疾病中调控炎症小体活化的研究进展[J]. 遗传, 2023, 45(11): 1007-1017.

Shuting Quan, Weiwei Jiao, Fang Xu, Lin Sun, Hui Qi, Adong Shen. Advances in the regulation of inflammasome activation by GBP family in infectious diseases[J]. Hereditas(Beijing), 2023, 45(11): 1007-1017.

图/表 5

图1

表1

GBP家族成员在炎症小体活化中的作用"

GBP家族成员	炎症小体活化类型	炎症小体活化途径	病原体	参考文献
GBP1	经典	GBP1水解GTP后产生GMP，GMP被进一步分解代谢为尿酸，通过经典途径活化NLRP3炎症小体，引起成熟的caspase-1水平升高，促进IL-1β分泌以及细胞焦亡发生。	沙眼衣原体	[40]
GBP1	非经典	(1)HeLa细胞中，GBP1作为胞质内的PRR结合细菌外膜的LPS，招募GBP2、GBP3和GBP4形成在细菌表面形成一个信号平台，进而招募caspase-4到此平台，GBP1、GBP3、caspase-4和LPS通过相互作用，引起caspase-4介导的非经典途径炎症小体活化、细胞焦亡以及IL-18分泌。其中，GBP1可能通过其GTPase结构域结合LPS的脂质A和/或内核，caspase-4的CARD与LPS的脂质A结合。 (2)巨噬细胞中，GBP1靶向于含有鼠伤寒沙门氏菌的液泡，并且招募caspase-4靶向液泡以及活化。	鼠伤寒沙门氏菌	[24,41]
GBP2	经典	GBP2在新凶手弗朗西丝菌感染中小鼠的巨噬细胞中促进经典途径AIM2炎症小体活化，并且促进大肠杆菌OMVs通过经典途径活化NLRP3炎症小体。	新凶手弗朗西丝菌、大肠杆菌	[43,45,46]
GBP2	非经典	受GBP1招募组成信号平台促进非经典途径炎症小体活化外(见GBP1非经典炎症小体活化)。	鼠伤寒沙门氏菌	[24,41,44]
GBP5	经典	(1)LPS或鼠伤寒沙门氏菌作用后，GBP5可以促进巨噬细胞中NLRP3-ASC炎症小体的组装。其中，GBP5和NLRP3的pyrin 结构域之间的相互作用促进ASC聚合。 (2)GBP5是新凶手弗朗西丝菌感染小鼠巨噬细胞中重要的AIM2炎症小体激活剂，并促进胞浆细菌溶解。	鼠伤寒沙门氏菌、新凶手弗朗西丝菌	[13,43,45]
GBP5	非经典	布鲁氏杆菌感染中，GBP5是促进caspase-11对LPS识别的关键分子，可显著影响IL-1β分泌和LDH释放。	布鲁氏杆菌	[51]

表1

图2

图3

表2

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鸟苷酸结合蛋白家族在感染性疾病中调控炎症小体活化的研究进展

Advances in the regulation of inflammasome activation by GBP family in infectious diseases

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病原体类型	病原体	具体机制	参考文献
细菌	嗜肺军团菌	GBP蛋白可以使胞质内的菌体DNA释放到胞质中，通过非经典途径促进caspase-11活化，促进机体的免疫应答	[52]
	BCG	mGBP1和mGBP10通过将吞噬细胞氧化酶或抗菌肽传递到含有BCG的吞噬体中，对胞内菌起到杀伤作用	[38]
	鼠伤寒沙门氏菌	GBP1靶向鼠伤寒沙门氏菌液泡，导致含沙门氏菌液泡破裂，沙门氏菌进入宿主细胞的胞质内，通过非经典途径促进caspase-4活化并诱导细胞焦亡	[53]
	福氏志贺菌	GBP1和GBP2均能在S. flexneri表面形成LPS-蛋白复合物，通过非经典途径促进caspase-4活化，进而促进宿主对病原菌的免疫应答。同时，限制S. flexneri的运动能力和菌在细胞间的播散	[54,55]
	新凶手弗朗西斯菌	详见表1	[43]
	单核细胞增生性李斯特单胞菌	单核细胞增生性李斯特单胞菌感染巨噬细胞中，GBP5可以通过经典途径促进NLRP3炎症小体活化	[13]
	布鲁氏杆菌	详见表1	[51]
病毒	SARS-CoV-2	GBP2和GBP5通过抑制新型冠状病毒(severe acute respiratory syndrome coronavirus 2，SARS-CoV-2)分离株中的早期谱系的刺突蛋白的裂解，减弱病毒的传染性	[56]
病毒	HIV-1	GBP5在HIV-1的靶细胞——巨噬细胞中表达，通过干扰病毒包膜糖蛋白(envelope glycoprotein，Env)的加工和病毒粒子掺入来减弱病毒的感染性	[5]
寄生虫	弓形虫	鼠型GBP2蛋白通过其C端结构域作用于弓形虫寄居的纳虫泡，进而抑制弓形虫的增殖	[42]
其他	沙眼衣原体	详见表1	[40]