Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Viral and Rickettsial Diseases Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
Infect Immun. 2017 Dec 19;86(1). doi: 10.1128/IAI.00596-17. Print 2018 Jan.
, an obligate intracellular bacterium that is auxotrophic for the aromatic amino acids and histidine, causes scrub typhus, a potentially deadly infection that threatens 1 billion people. growth is minimal during the first 24 to 48 h of infection but its growth becomes logarithmic thereafter. How the pathogen modulates cellular functions to support its growth is poorly understood. The unfolded protein response (UPR) is a cytoprotective pathway that relieves endoplasmic reticulum (ER) stress by promoting ER-associated degradation (ERAD) of misfolded proteins. Here, we show that invokes the UPR in the first 48 h and benefits from ER stress in an amino acid-dependent manner. also impedes ERAD during this time period. By 72 h, ER stress is alleviated and ERAD proceeds unhindered. Sustained inhibition of ERAD using RNA interference results in an growth defect at 72 h that can be rescued by amino acid supplementation. Thus, temporally stalls ERAD until ERAD-derived amino acids are needed to support its growth. The effector Ank4 is linked to this phenomenon. Ank4 interacts with Bat3, a eukaryotic chaperone that is essential for ERAD, and is transiently expressed by during the infection period when it inhibits ERAD. Ectopically expressed Ank4 blocks ERAD to phenocopy infection. Our data reveal a novel mechanism by which an obligate intracellular bacterial pathogen modulates ERAD to satisfy its nutritional virulence requirements.
恙虫病东方体是一种专性细胞内细菌，对芳香族氨基酸和组氨酸有营养缺陷性，会导致恙虫病，这是一种潜在的致命感染，威胁着 10 亿人的生命。在感染的前 24 至 48 小时内，它的生长非常缓慢，但此后其生长呈对数增长。病原体如何调节细胞功能来支持其生长，这方面的了解还很有限。未折叠蛋白反应（UPR）是一种细胞保护途径，通过促进错误折叠蛋白的内质网（ER）相关降解（ERAD）来缓解内质网（ER）应激。在这里，我们表明，恙虫病东方体在最初的 48 小时内会引发 UPR，并以依赖氨基酸的方式受益于 ER 应激。恙虫病东方体还在这段时间内阻碍 ERAD。到 72 小时时，ER 应激得到缓解，ERAD 不受阻碍地进行。通过 RNA 干扰持续抑制 ERAD 会导致 72 小时时的生长缺陷，而通过氨基酸补充可以挽救这种缺陷。因此，恙虫病东方体暂时停止 ERAD，直到需要 ERAD 衍生的氨基酸来支持其生长。效应因子 Ank4 与这一现象有关。Ank4 与 Bat3 相互作用，Bat3 是一种真核伴侣，对 ERAD 至关重要，在感染期间，恙虫病东方体短暂表达 Ank4，从而抑制 ERAD。异位表达的 Ank4 会阻断 ERAD，从而模拟恙虫病东方体的感染。我们的数据揭示了一种新的机制，即一种专性细胞内细菌病原体如何调节 ERAD 以满足其营养毒性要求。
