Howard Hughes Medical Insitute, Boston, MA 02115.
Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2020 Nov 24;117(47):29862-29871. doi: 10.1073/pnas.2010723117. Epub 2020 Nov 10.
Organelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogen led us to discover that type I IFN (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I signaling modified the localization, acidification, protease activity, and proteomic profile of lysosomes. Proteomic and genetic analyses revealed that multiple IFN-I-stimulated genes including , , and contribute to lysosome acidification. IFN-I-dependent lysosome acidification was associated with elevated intracellular virulence gene expression, rupture of the -containing vacuole, and host cell death. Moreover, IFN-I signaling promoted in vivo pathogenesis in the intestinal epithelium where initiates infection, indicating that IFN-I signaling can modify innate defense in the epithelial compartment. We propose that IFN-I control of lysosome function broadly impacts host defense against diverse viral and microbial pathogens.
细胞器重编程对于细胞内稳态至关重要，但宿主在微生物感染期间控制细胞器功能的因素在很大程度上仍未被阐明。在这里，我们对肠道上皮细胞中典型的细胞内细菌病原体 进行了全基因组规模的 CRISPR/Cas9 筛选，结果发现 I 型干扰素 (IFN-I) 重塑了溶酶体。即使在没有感染的情况下，IFN-I 信号也会改变溶酶体的定位、酸化、蛋白酶活性和蛋白质组谱。蛋白质组学和遗传分析表明，多种 IFN-I 刺激的基因，包括 、 和 ，有助于溶酶体酸化。IFN-I 依赖性溶酶体酸化与细胞内 的毒力基因表达升高、含 的液泡破裂和宿主细胞死亡有关。此外，IFN-I 信号转导促进了 在肠道上皮细胞中的体内发病机制， 在此处开始感染，这表明 IFN-I 信号转导可以修饰上皮细胞中先天防御。我们提出，IFN-I 控制溶酶体功能广泛影响宿主对各种病毒和微生物病原体的防御。
