PLD4
Phospholipase D family member 4 is an enzyme that in humans is encoded by the PLD4 gene.
Tissue distribution
PLD4 is expressed in immune cells such as B cells, macrophages and especially dendritic cells. A subtype of dendritic cells known as the plasmacytoid dendritic cells has the highest expression of PLD4, among its top 10 most abundant transcripts.
Structure
PLD4 is a type II transmembrane protein, with its short N-terminal domain inside the cytoplasm, and catalytic C-terminus outside the plasma membrane. Structurally, the extracellular domain of PLD4 protein has two HKD motifs, forming its catalytic center. In crystal structure, two PLD4 proteins form a homodimer.
Function
Unlike other canonical members of the PLD family, PLD4 does not demonstrate phospholipase activity. Instead, PLD4 is known as an exonuclease that digests short ssDNA or ssRNA products in a 5' to 3' manner. The optimum pH for PLD4 to digest single stranded nucleic acid substrate is around 4.4 to 4.8, which coincides with its acidic late-endosomal / lysosomal subcellular location. Besides, it is also reported that PLD4, together with PLD3, participate in the synthesis of S,S-BMP, a phospholipid that is required for the degradation of lipids in lysosome. As an endolysosomal protein, PLD4 along with PLD3 digest nucleic acid product inside the lysosome of phagocytes to modulate the activity of nucleic acid sensors such as TLR9, TLR7 etc.
Genetic studies have associate PLD4 with several autoimmune diseases, such as SLE, rheumatoid arthritis and systemic sclerosis. Loss-of-function mutations in PLD4 are reported to trigger overactivation of the immune system by type I interferon pathways and SLE in both mouse model and human patients, and zinc deficiency-like syndrome in cattle.