Interferon gamma-inducible protein 16(IFI16)senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear(HIN)domains,HINa and HINb,through the cooperative assembly of IFI1...Interferon gamma-inducible protein 16(IFI16)senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear(HIN)domains,HINa and HINb,through the cooperative assembly of IFI16 filaments on double-stranded DNA(dsDNA).The role of HINa in sensing DNA is not clearly understood.Here,we describe the crystal structure of the HINa domain in complex with DNA at 2.55A°resolution and provide the first insight into the mode of DNA binding by the HINa domain.The structure reveals the presence of two oligosaccharide/nucleotide-binding(OB)folds with a unique DNA-binding surface.HINa uses loop L45 of the canonical OB2 fold to bind to the DNA backbone.The dsDNA is recognized as two single strands of DNA.Interestingly,deletion of HINb compromises the ability of IFI16 to induce IFN-b,while HINa mutants impaired in DNAbinding enhance the production of IFN-b.These results shed light on the roles of IFI16 HIN domains in DNA recognition and innate immune responses.展开更多
EB病毒(Epstein-Barr virus,EBV)在人群中普遍易感,其感染可累及血液、呼吸、泌尿、消化、神经等全身多个系统,亦在相关肿瘤、自身免疫病等疾病发展中扮演重要角色,严重威胁人类健康。作为一种DNA病毒,EBV可被固有免疫应答中的DNA识别...EB病毒(Epstein-Barr virus,EBV)在人群中普遍易感,其感染可累及血液、呼吸、泌尿、消化、神经等全身多个系统,亦在相关肿瘤、自身免疫病等疾病发展中扮演重要角色,严重威胁人类健康。作为一种DNA病毒,EBV可被固有免疫应答中的DNA识别受体感知,触发下游一系列免疫应答。DNA识别通路由DNA感受器、接头分子及下游效应信号组成。双链DNA感受器主要包括黑色素瘤缺乏因子2样受体(absent in melanoma 2-like receptors,ALRs)、环状GMP-AMP合酶(cyclic GMP-AMP synthase,cGAS)等;接头分子主要是干扰素基因刺激因子(stimulator of interferon genes,STING)和含有caspase招募结构域的凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing a caspase recruitment domain,ASC);下游免疫效应主要包括Ⅰ型IFN、炎性小体及促炎细胞因子等。作为一种疱疹病毒科的双链DNA病毒,EBV可触发宿主复杂的固有免疫和适应性免疫应答,尤其是多种DNA识别受体介导的通路,在宿主免疫防御及病原体免疫逃避等方面均发挥关键作用。本文以DNA感受器为线索,全面总结近年来DNA识别信号在EBV感染中的活化作用、调控机制及临床相关性,以进一步理解EBV感染后宿主的固有免疫应答,为EBV感染引起的相关疾病的防治提供免疫学依据。展开更多
基金supported by the National Natural Science Foundation of China(grant no.31570875,31330019,31200559,and 81590761)the Ministry of Science and Technology of China(grant no.2014CB910400 and 2013CB911103)+2 种基金the National Science and Technology Major Project of China(grant no.2013ZX10004-602)the Beijing Nova Program(grant no.Z141102001814020)Youth Innovation Promotion Association CAS,and the special project of Ebola virus research from the president foundation of Chinese Academy of Sciences.
文摘Interferon gamma-inducible protein 16(IFI16)senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear(HIN)domains,HINa and HINb,through the cooperative assembly of IFI16 filaments on double-stranded DNA(dsDNA).The role of HINa in sensing DNA is not clearly understood.Here,we describe the crystal structure of the HINa domain in complex with DNA at 2.55A°resolution and provide the first insight into the mode of DNA binding by the HINa domain.The structure reveals the presence of two oligosaccharide/nucleotide-binding(OB)folds with a unique DNA-binding surface.HINa uses loop L45 of the canonical OB2 fold to bind to the DNA backbone.The dsDNA is recognized as two single strands of DNA.Interestingly,deletion of HINb compromises the ability of IFI16 to induce IFN-b,while HINa mutants impaired in DNAbinding enhance the production of IFN-b.These results shed light on the roles of IFI16 HIN domains in DNA recognition and innate immune responses.
文摘EB病毒(Epstein-Barr virus,EBV)在人群中普遍易感,其感染可累及血液、呼吸、泌尿、消化、神经等全身多个系统,亦在相关肿瘤、自身免疫病等疾病发展中扮演重要角色,严重威胁人类健康。作为一种DNA病毒,EBV可被固有免疫应答中的DNA识别受体感知,触发下游一系列免疫应答。DNA识别通路由DNA感受器、接头分子及下游效应信号组成。双链DNA感受器主要包括黑色素瘤缺乏因子2样受体(absent in melanoma 2-like receptors,ALRs)、环状GMP-AMP合酶(cyclic GMP-AMP synthase,cGAS)等;接头分子主要是干扰素基因刺激因子(stimulator of interferon genes,STING)和含有caspase招募结构域的凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing a caspase recruitment domain,ASC);下游免疫效应主要包括Ⅰ型IFN、炎性小体及促炎细胞因子等。作为一种疱疹病毒科的双链DNA病毒,EBV可触发宿主复杂的固有免疫和适应性免疫应答,尤其是多种DNA识别受体介导的通路,在宿主免疫防御及病原体免疫逃避等方面均发挥关键作用。本文以DNA感受器为线索,全面总结近年来DNA识别信号在EBV感染中的活化作用、调控机制及临床相关性,以进一步理解EBV感染后宿主的固有免疫应答,为EBV感染引起的相关疾病的防治提供免疫学依据。
