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

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Cell-autonomous defense is crucial for controlling infections.
• Interferon-gamma (IFN-γ) induces numerous host proteins, many uncharacterized.
• Apolipoproteins are known for lipid transport, not intracellular defense.

Purpose of the Study:

• To identify novel IFN-γ-induced proteins involved in host defense.
• To characterize the function of apolipoprotein L3 (APOL3) in cellular immunity.

Main Methods:

• CRISPR-Cas9 mutagenesis screen of 19,050 human genes.
• Native mass spectrometry and single-particle cryo-electron microscopy.
• Bactericidal assays in non-immune barrier cell types.

Main Results:

• Identified APOL3 as an IFN-γ-induced bactericidal protein.
• APOL3 targets intracellular bacteria, dissolving their anionic membranes.
• Formation of human-bacterial lipoprotein nanodiscs was observed.
• APOL3 protects diverse non-immune cells against infection.

Conclusions:

• APOL3 acts as an intracellular lysin, repurposing apolipoprotein functions for defense.
• This mechanism provides sterilizing immunity in resident non-immune cells.
• Highlights a novel host defense strategy against intracellular pathogens.