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

Activation of cell-autonomous defense by the immune cytokine interferon-gamma (IFN-gamma) is critical to the control of life-threatening infections in humans. IFN-gamma 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-gamma-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.

Automated summary

Activation of cell-autonomous defense by IFN-gamma induces the expression of APOL3, which acts as a potent bactericidal agent protecting non-immune barrier cell types against infection. This reveals a novel mechanism through which human cells can achieve sterilizing immunity.