PLD3 (phospholipase D family member 3) functions as a 5'→3' single-stranded DNA and RNA exonuclease that regulates endosomal nucleic acid sensing and immune responses 1. The protein degrades single-stranded nucleic acids in endolysosomal compartments, processing self and pathogenic DNA/RNA molecules that could serve as danger signals for innate immune receptors like toll-like receptors (TLRs) 1. PLD3 works cooperatively with endonuclease RNase T2 to generate specific RNA ligands for TLR7 activation, releasing 2',3'-cyclic guanosine monophosphate and cytidine-rich RNA fragments that trigger antiviral immune responses 2. Additionally, PLD3 functions as a transphosphatidylase that synthesizes (S,S)-bis(monoacylglycero)phosphate (BMP), a crucial lysosomal phospholipid required for lipid degradation, particularly gangliosides 3. The protein regulates endolysosomal homeostasis and impacts cellular removal of dysfunctional organelles via autophagy 3. Clinically, PLD3 is associated with spinocerebellar ataxia 46 and has been identified as a risk factor for late-onset Alzheimer's disease through rare coding variants 45. PLD3 expression is downregulated in Alzheimer's disease brains, negatively correlating with amyloid precursor protein and amyloid-β levels 5.