Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida.
Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida.
复制标题
鸟苷酸盐结合蛋白在弗朗西斯氏菌（Francisella novicida）感染过程中促进了AIM2炎症体的激活。
DOI：
10.1038/ni.3119
复制
发表时间：
2015-05
影响因子：
30.5
通讯作者：
Broz P
中科院分区：
文献类型：
--
作者：
Meunier E;Wallet P;Dreier RF;Costanzo S;Anton L;Rühl S;Dussurgey S;Dick MS;Kistner A;Rigard M;Degrandi D;Pfeffer K;Yamamoto M;Henry T;Broz P
AIM2炎性小体检测细胞质中的双链DNA，诱导caspase-1依赖性的焦亡以及炎症细胞因子IL-1β和IL-18的释放。AIM2对于宿主防御在细胞质中复制的DNA病毒和细菌（如新弗朗西斯菌）至关重要。新发F. novicida激活AIM2需要溶菌，但这一过程是偶然的还是宿主驱动的免疫机制尚不清楚。通过siRNA筛选近500个干扰素刺激基因，我们发现鸟苷酸结合蛋白GBP2和GBP5是新真菌感染过程中关键的AIM2激活因子。它们的突出作用在体外和兔热病小鼠模型中得到了验证。从机制上讲，这两种GBPs靶向细胞质内的新乳杆菌并促进细菌溶解。因此，除了它们在宿主防御空泡病原体中的作用外，GBPs还通过直接攻击细胞质细菌来促进配体的呈现。
The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines IL-1β and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella novicida. AIM2 activation by F. novicida requires bacteriolysis, yet whether this process is accidental or a host-driven immune mechanism remained unclear. Using siRNA screening for nearly 500 interferon-stimulated genes, we identified guanylate-binding proteins GBP2 and GBP5 as key AIM2 activators during F. novicida infection. Their prominent role was validated in vitro and in a mouse model of tularemia. Mechanistically, these two GBPs target cytosolic F. novicida and promote bacteriolysis. Thus, besides their role in host defense against vacuolar pathogens, GBPs also facilitate the presentation of ligands by directly attacking cytosolic bacteria.