PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleicacid sensing

Abstract

Abstract Genome-wide association studies have linked the gene encoding phospholipase D3 (PLD3) to Alzheimer’s disease and have linked PLD4 to rheumatoid arthritis and systemic sclerosis. PLD3 and PLD4 are endolysosomal proteins that we recently discovered are nucleases. PLD4-deficient mice have an inflammatory disease, marked by elevated levels of interferon-γ (IFN-γ) and splenomegaly. These phenotypes are blocked in the absence of TLR9. PLD3−/− mice have a relatively benign phenotype. Mice deficient in both PLD3 and PLD4 developed lethal liver inflammation in early life, which was blocked on a Unc93b-3d/3d background. These data suggest that PLD3 and PLD4 enzymes play important roles in the regulation of endosomal TLR signaling.