5'->3' DNA exonuclease which digests single-stranded DNA (ssDNA) (PubMed:30111894). Regulates inflammatory cytokine responses via the degradation of nucleic acids, by reducing the concentration of ssDNA able to stimulate TLR9, a nucleotide-sensing receptor in collaboration with PLD4 (PubMed:30111894). May be important in myotube formation. Plays a role in lysosomal homeostasis. Involved in the regulation of endosomal protein sorting (By similarity). Exonucleolytic cleavage in the 5'- to 3'-direction to yield nucleoside 3'-phosphates. Optimum pH is 5.5-5. Interacts with APP. Localizes to ER-associated vesicles in differentiating myotubes. The soluble form in lysosome arises by proteolytic processing of the membrane-bound form. Expressed at higher level in brain than in non-nervous tissue. Expressed in mature neurons of the forebrain and appears to be turned on at late stages of neurogenesis. Expressed during late neuronal development in the forebrain (PubMed:9813063). Expressed in the pyramidal neurons of the cortex and hippocampus (PubMed:28128235). Low expression in the cerebellum (PubMed:30312375). Up-regulated during myoblast differentiation into myotubes. N-glycosylated. Proteolytically processed to a soluble form that is stable within endosomes and lysosomes. During transport through the secretory pathway becomes proteolysed by cysteine proteases, thereby releasing a stable soluble lysosomal lumenal polypeptide, whereas the transmembrane-bound fragment is rapidly degraded. Its transport route to lysosomes involves ubiquitination and the ESCRT complex. Ubiquitinated. Ubiquitination mediates sorting into lysosomes. Deficient mice exhibit no altered phenotype except a exaggerated response of macrophages to TLR9 (PubMed:30111894). Morphology of PLD3-deficient brains does not reveal any major abnormalities but an altered lysosomal structure (PubMed:29386126). PDL3 and PLD4 double-deficient mice are unable to survive beyond the age of 21 days due to severe liver inflammation (PubMed:30111894). Livers from double-knockout mice develop lethal hepatic autoinflammatory disease that could be prevented by a single allele of either PDL3 or PLD4 (PubMed:30111894). Belongs to the phospholipase D family. It was initially thought that PDL3 has phospholipase D activity due to its HKD motifs. The second HKD motif contains Glu instead of the canonical Asp. Its enzyme activity is therefore unsure. Catalytic phospholipase D activity is still controversial (PubMed:30312375, PubMed:9813063) (By similarity). Its closest homolog PLD4, exhibits no phospholipase activity (By similarity).