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

Activation of cell-autonomous defense by the immune cytokine interferon-? (IFN-?) is critical to the control of life-threatening infections in humans. IFN-? 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-?-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.
Mesh Terms:
Apolipoproteins L, Bacterial Outer Membrane, Bacteriolysis, CRISPR-Cas Systems, Cell Membrane, Cell Membrane Permeability, Cells, Cultured, Cytosol, Detergents, GTP-Binding Proteins, Gene Editing, Gram-Negative Bacteria, Humans, Immunity, Innate, Interferon-gamma, Lipoproteins, Microbial Viability, O Antigens, Protein Domains, Salmonella typhimurium, Solubility
Science
Date: Dec. 16, 2020
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