Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Microbiology and Immunology, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada.
Michael Smith Laboratories, University of British Columbia (UBC), 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada; Department of Microbiology and Immunology, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Centre for Blood Research, UBC, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
Immunity. 2019 Feb 19;50(2):418-431.e6. doi: 10.1016/j.immuni.2019.01.014. Epub 2019 Feb 12.
Sepsis is a bi-phasic inflammatory disease that threatens approximately 30 million lives and claims over 14 million annually, yet little is known regarding the molecular switches and pathways that regulate this disease. Here, we have described ABCF1, an ATP-Binding Cassette (ABC) family member protein, which possesses an E2 ubiquitin enzyme activity, through which it controls the Lipopolysaccharide (LPS)- Toll-like Receptor-4 (TLR4) mediated gram-negative insult by targeting key proteins for K63-polyubiquitination. Ubiquitination by ABCF1 shifts the inflammatory profile from an early phase MyD88-dependent to a late phase TRIF-dependent signaling pathway, thereby regulating TLR4 endocytosis and modulating macrophage polarization from M1 to M2 phase. Physiologically, ABCF1 regulates the shift from the inflammatory phase of sepsis to the endotoxin tolerance phase, and modulates cytokine storm and interferon-β (IFN-β)-dependent production by the immunotherapeutic mediator, SIRT1. Consequently, ABCF1 controls sepsis induced mortality by repressing hypotension-induced renal circulatory dysfunction.
败血症是一种双相炎症性疾病，威胁着约 3000 万人的生命，每年夺走超过 1400 万人的生命，但人们对调节这种疾病的分子开关和途径知之甚少。在这里，我们描述了 ABCF1，一种 ATP 结合盒（ABC）家族成员蛋白，它具有 E2 泛素酶活性，通过该活性，它通过对关键蛋白进行 K63-多泛素化来控制脂多糖（LPS）-Toll 样受体 4（TLR4）介导的革兰氏阴性损伤。ABCF1 的泛素化将炎症特征从早期的 MyD88 依赖阶段转变为晚期的 TRIF 依赖信号通路，从而调节 TLR4 的内吞作用，并调节巨噬细胞从 M1 期向 M2 期的极化。从生理上讲，ABCF1 调节败血症从炎症期向内毒素耐受期的转变，并调节细胞因子风暴和免疫治疗介质 SIRT1 依赖 IFN-β的产生。因此，ABCF1 通过抑制低血压引起的肾循环功能障碍来控制败血症引起的死亡率。
