Activation of cell-autonomous defense by the immune cytokine interferon-γ (IFN-γ) is critical to the control of life-threatening infections in humans. IFN-γ induces the expression of hundreds of host proteins in all nucleated cells and tissues, yet many of these proteins remain uncharacterized. We screened 19,050 human genes by CRISPR-Cas9 mutagenesis and identified IFN-γ–induced apolipoprotein L3 (APOL3) as a potent bactericidal agent protecting multiple non–immune barrier cell types against infection. Canonical apolipoproteins typically solubilize mammalian lipids for extracellular transport; APOL3 instead targeted cytosol-invasive bacteria to dissolve their anionic membranes into human-bacterial lipoprotein nanodiscs detected by native mass spectrometry and visualized by single-particle cryo–electron microscopy. Thus, humans have harnessed the detergent-like properties of extracellular apolipoproteins to fashion an intracellular lysin, thereby endowing resident nonimmune cells with a mechanism to achieve sterilizing immunity.

免疫细胞因子干扰素-γ (IFN-γ) 激活细胞自主防御对于控制人类危及生命的感染至关重要。 IFN-γ 可诱导所有有核细胞和组织中数百种宿主蛋白​​的表达，但其中许多蛋白仍未被表征。我们通过 CRISPR-Cas9 诱变筛选了 19,050 个人类基因，并鉴定出 IFN-γ 诱导的载脂蛋白 L3 (APOL3) 是一种有效的杀菌剂，可保护多种非免疫屏障细胞类型免受感染。典型的载脂蛋白通常溶解哺乳动物脂质以进行细胞外运输；相反，APOL3 靶向细胞质侵入细菌，将其阴离子膜溶解到人类细菌脂蛋白纳米盘中，通过天然质谱检测并通过单粒子冷冻电子显微镜可视化。因此，人类利用细胞外载脂蛋白的洗涤剂样特性来形成细胞内溶素，从而赋予常驻非免疫细胞一种实现灭菌免疫的机制。