A human apolipoprotein L with detergent-like activity kills intracellular pathogens.
Ryan G GaudetShiwei ZhuAnushka HalderBae-Hoon KimClinton J BradfieldShuai HuangDijin XuAgnieszka MaminskaThanh Ngoc NguyenMichael LazarouErdem KaratekinKallol GuptaJohn D MacMickingPublished in: Science (New York, N.Y.) (2021)
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.
Keyphrases
- endothelial cells
- crispr cas
- mass spectrometry
- dendritic cells
- induced apoptosis
- electron microscopy
- immune response
- single cell
- genome editing
- high glucose
- induced pluripotent stem cells
- cell cycle arrest
- high resolution
- poor prognosis
- gene expression
- cell therapy
- stem cells
- oxidative stress
- cell proliferation
- dna methylation
- reactive oxygen species
- high performance liquid chromatography
- capillary electrophoresis
- tandem mass spectrometry
- gas chromatography