Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, VA, USA.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, School of Medicine, Charlottesville, VA, USA.
Nat Commun. 2024 Sep 14;15(1):8069. doi: 10.1038/s41467-024-52119-6.
How intracellular bacteria subvert the major histocompatibility complex (MHC) class I pathway is poorly understood. Here, we show that the obligate intracellular bacterium Orientia tsutsugamushi uses its effector protein, Ank5, to inhibit nuclear translocation of the MHC class I gene transactivator, NLRC5, and orchestrate its proteasomal degradation. Ank5 uses a tyrosine in its fourth ankyrin repeat to bind the NLRC5 N-terminus while its F-box directs host SCF complex ubiquitination of NLRC5 in the leucine-rich repeat region that dictates susceptibility to Orientia- and Ank5-mediated degradation. The ability of O. tsutsugamushi strains to degrade NLRC5 correlates with ank5 genomic carriage. Ectopically expressed Ank5 that can bind but not degrade NLRC5 protects the transactivator during Orientia infection. Thus, Ank5 is an immunoevasin that uses its bipartite architecture to rid host cells of NLRC5 and reduce surface MHC class I molecules. This study offers insight into how intracellular pathogens can impair MHC class I expression.
细胞内细菌如何颠覆主要组织相容性复合体 (MHC) I 类途径尚不清楚。在这里，我们表明，专性细胞内细菌恙虫东方体使用其效应蛋白 Ank5 抑制 MHC I 类基因转录激活物 NLRC5 的核易位，并协调其蛋白酶体降解。Ank5 使用其四重复的酪氨酸结合 NLRC5 的 N 端，而其 F -box 则在富含亮氨酸重复区域指导 NLRC5 易受恙虫和 Ank5 介导的降解的情况下，指导宿主 SCF 复合物对 NLRC5 的泛素化。 Orientia 和 Ank5 介导的降解。恙虫东方体菌株降解 NLRC5 的能力与 ank5 基因组携带有关。能够结合但不能降解 NLRC5 的异位表达 Ank5 在 Orientia 感染期间保护转录激活物。因此，Ank5 是一种免疫逃逸蛋白，它利用其双功能结构去除宿主细胞中的 NLRC5 并减少表面 MHC I 类分子。这项研究提供了对细胞内病原体如何削弱 MHC I 类表达的深入了解。
