McCormack Ryan M, Lyapichev Kirill, Olsson Melissa L, Podack Eckhard R, Munson George P
Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States.
Elife. 2015 Sep 29;4:e06505. doi: 10.7554/eLife.06505.
Perforin-2 (MPEG1) is an effector of the innate immune system that limits the proliferation and spread of medically relevant Gram-negative, -positive, and acid fast bacteria. We show here that a cullin-RING E3 ubiquitin ligase (CRL) complex containing cullin-1 and βTrCP monoubiquitylates Perforin-2 in response to pathogen associated molecular patterns such as LPS. Ubiquitylation triggers a rapid redistribution of Perforin-2 and is essential for its bactericidal activity. Enteric pathogens such as Yersinia pseudotuberculosis and enteropathogenic Escherichia coli disarm host cells by injecting cell cycle inhibiting factors (Cifs) into mammalian cells to deamidate the ubiquitin-like protein NEDD8. Because CRL activity is dependent upon NEDD8, Cif blocks ubiquitin dependent trafficking of Perforin-2 and thus, its bactericidal activity. Collectively, these studies further underscore the biological significance of Perforin-2 and elucidate critical molecular events that culminate in Perforin-2-dependent killing of both intracellular and extracellular, cell-adherent bacteria.
穿孔素-2（MPEG1）是先天性免疫系统的一种效应分子，可限制医学上相关的革兰氏阴性菌、革兰氏阳性菌和抗酸菌的增殖与扩散。我们在此表明，一种包含cullin-1和βTrCP的cullin-RING E3泛素连接酶（CRL）复合物会响应诸如脂多糖等病原体相关分子模式，对穿孔素-2进行单泛素化修饰。泛素化会引发穿孔素-2的快速重新分布，并且对其杀菌活性至关重要。诸如假结核耶尔森菌和肠致病性大肠杆菌等肠道病原体通过向哺乳动物细胞中注射细胞周期抑制因子（Cifs）以使类泛素蛋白NEDD8脱酰胺，从而解除宿主细胞的防御。由于CRL活性依赖于NEDD8，Cif会阻断穿孔素-2的泛素依赖性转运，进而阻断其杀菌活性。总的来说，这些研究进一步强调了穿孔素-2的生物学意义，并阐明了最终导致穿孔素-2依赖的细胞内和细胞外、细胞黏附细菌杀伤的关键分子事件。
