National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01AI068041-14
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01AI108834-07
米国
Howard Hughes Medical Institute (HHMI)
米国
引用
ジャーナル: Science / 年: 2021 タイトル: A human apolipoprotein L with detergent-like activity kills intracellular pathogens. 著者: Ryan G Gaudet / Shiwei Zhu / Anushka Halder / Bae-Hoon Kim / Clinton J Bradfield / Shuai Huang / Dijin Xu / Agnieszka Mamiñska / Thanh Ngoc Nguyen / Michael Lazarou / Erdem Karatekin / ...著者: Ryan G Gaudet / Shiwei Zhu / Anushka Halder / Bae-Hoon Kim / Clinton J Bradfield / Shuai Huang / Dijin Xu / Agnieszka Mamiñska / Thanh Ngoc Nguyen / Michael Lazarou / Erdem Karatekin / Kallol Gupta / John D MacMicking / 要旨: 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 ...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.