Sun Lei, Zhang Haibo, Zhang Huihui, Lou Xinyi, Wang Zhiming, Wu Yaxian, Yang Xinyi, Chen Daijie, Guo Beining, Zhang Ao, Qian Feng
Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Pharm-X Center, Research Center for Small Molecule Immunological Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China.
Nat Microbiol. 2023 Jan;8(1):107-120. doi: 10.1038/s41564-022-01278-7. Epub 2023 Jan 2.
Staphylococcus aureus invades cells and persists intracellularly, causing persistent inflammation that is notoriously difficult to treat. Here we investigated host-pathogen interactions underlying intracellular S. aureus infection in macrophages and discovered that the endoplasmic reticulum (ER) is an important cellular compartment for intracellular S. aureus infection. Using CRISPR-Cas9 guide RNA library screening, we determined that the autocrine motility factor receptor (AMFR), an ER-resident E3 ubiquitin ligase, played an essential role in mediating intracellular S. aureus-induced inflammation. AMFR directly interacted with TAK1-binding protein 3 (TAB3) in the ER, inducing K27-linked polyubiquitination of TAB3 on lysine 649 and promoting TAK1 activation. Moreover, the virulence factor γ-haemolysin B (HIgB) of S. aureus bound to the AMFR and regulated TAB3. Our findings highlight an unknown role of AMFR in intracellular S. aureus infection-induced pneumonia and suggest that pharmacological interruption of AMFR-mediated TAB3 signalling cascades and HIgB targeting may prevent invasive staphylococci-mediated pneumonia.
金黄色葡萄球菌侵入细胞并在细胞内持续存在，引发难以治疗的持续性炎症。在此，我们研究了巨噬细胞内金黄色葡萄球菌感染背后的宿主-病原体相互作用，并发现内质网（ER）是细胞内金黄色葡萄球菌感染的重要细胞区室。通过CRISPR-Cas9向导RNA文库筛选，我们确定自分泌运动因子受体（AMFR），一种内质网驻留的E3泛素连接酶，在介导细胞内金黄色葡萄球菌诱导的炎症中起关键作用。AMFR在内质网中直接与TAK1结合蛋白3（TAB3）相互作用，诱导TAB3赖氨酸649位点的K27连接的多聚泛素化，并促进TAK1激活。此外，金黄色葡萄球菌的毒力因子γ-溶血素B（HIgB）与AMFR结合并调节TAB3。我们的研究结果突出了AMFR在细胞内金黄色葡萄球菌感染诱导的肺炎中的未知作用，并表明对AMFR介导的TAB3信号级联反应的药理学阻断以及对HIgB的靶向作用可能预防侵袭性葡萄球菌介导的肺炎。
