PLD4 is a 5'→3' exonuclease that hydrolyzes single-stranded DNA and RNA to form nucleoside 3'-monophosphates, displaying higher efficiency for uridine and guanosine-initiated substrates 1. Beyond nucleic acid degradation, PLD4 functions as a transphosphatidylase synthesizing (S,S)-bis(monoacylglycero)phosphate (BMP), the primary phospholipid of lysosomal intralumenal vesicles required for lipid degradation 2. PLD4 processes endolysosomal nucleic acids to regulate innate immunity: it degrades mitochondrial CpG-rich ssDNA to prevent TLR9 activation, while cooperating with endonuclease RNASET2 to generate 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) and pyrimidine-rich RNA fragments that activate TLR7 for antiviral responses 3. Loss-of-function PLD4 mutations cause systemic lupus erythematosus (SLE) through excessive TLR7 and TLR9 activation and hyperactivated type I interferon signaling in dendritic cells 4. PLD4-deficient mice exhibit autoimmunity with plasmacytoid dendritic cell and plasma cell expansion, responding to JAK inhibitor baricitinib therapy 4. PLD4 variants are associated with SLE susceptibility, producing altered anti-dsDNA antibody responses 5. Elevated CSF PLD4 correlates with neuroinflammation in Parkinson's disease LRRK2 carriers 6. These findings establish PLD4 as a critical regulator of endolysosomal homeostasis and immune tolerance.