美国耶鲁大学医学院John D. MacMicking研究组的最新研究发现了一种具有去污剂样活性的人载脂蛋白L可杀死细胞内的病原体。该项研究成果发表在2021年7月16日出版的《科学》杂志上。

研究人员利用CRISPR-Cas9对19,050个人类基因进行了诱变筛选，并揭示了干扰素-γ(IFN-γ)诱导的载脂蛋白L3 (APOL3) 是保护多种非免疫屏障细胞免受感染的有效杀菌因子。典型载脂蛋白的功能是溶解哺乳动物脂质以完成细胞外运输；相反APOL3可靶向侵入细胞溶胶的细菌，将它们的阴离子膜溶解到可通过质谱检测以及单粒子冷冻电镜观察的人细菌脂蛋白纳米圆盘中。因此，人细胞已经进化出利用细胞外载脂蛋白的去垢剂样特性来形成细胞内溶素的能力，这赋予常驻非免疫细胞杀菌免疫的功能。

据了解，细胞免疫因子IFN-γ激活的细胞自防御系统对于调控可威胁人生命的感染至关重要。IFN-γ在所有有核细胞和组织中诱导了数百种宿主蛋白的表达，但其中许多蛋白质仍未得到表征。

附：英文原文

Title: A human apolipoprotein L with detergent-like activity kills intracellular pathogens

Author: Ryan G. Gaudet, Shiwei Zhu, Anushka Halder, Bae-Hoon Kim, Clinton J. Bradfield, Shuai Huang, Dijin Xu, Agnieszka Mamiska, Thanh Ngoc Nguyen, Michael Lazarou, Erdem Karatekin, Kallol Gupta, John D. MacMicking

Issue&Volume: 2021/07/16

Abstract: 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.

DOI: 10.1126/science.abf8113

Source: https://science.sciencemag.org/content/373/6552/eabf8113