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.

脓毒症是一种双相性炎症性疾病，每年威胁大约3000万人的生命，每年造成1400万人死亡，但对于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，具有E2泛素酶活性，通过它控制脂多糖（LPS）-Toll样受体4（TLR4）介导的革兰氏阴性通过靶向关键蛋白进行K63多泛素化来进行侮辱。ABCF1的泛素化使炎症反应从早期的MyD88依赖性转变为晚期的TRIF依赖性信号传导途径，从而调节TLR4内吞作用并将巨噬细胞极化作用从M1转变为M2。在生理上 ABCF1调节败血症从炎症期到内毒素耐受期的转变，并通过免疫治疗介质SIRT1调节细胞因子风暴和干扰素-β（IFN-β）依赖性产生。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。