Biology:PLD4

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Short description: Enzyme found in Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Phospholipase D family member 4 is an enzyme that in humans is encoded by the PLD4 gene.[1][2]

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 (pDC) has the highest expression of PLD4, among its top 10 most abundant transcripts.[3]

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. [4]

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.[5][6] 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.[4] 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.[7] 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 and etc. [5][6][8]

Clinical sigfnicance

Genetic studies have associate PLD4 with several autoimmune diseases, such as SLE, rheumatoid arthritis and systemic sclerosis.[9][10][11] 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.[9][12][13]

References

  1. ↑ "Entrez Gene: Phospholipase D family, member 4". https://www.ncbi.nlm.nih.gov/gene/122618. 
  2. ↑ Universal protein resource accession number Q96BZ4 for "PLD4 - Phospholipase D4 - Homo sapiens" at UniProt.
  3. ↑ "PLD4 - The Human Protein Atlas". https://www.proteinatlas.org/search/PLD4. 
  4. ↑ 4.0 4.1 "Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4" (in English). Structure 32 (6): 766–779.e7. June 2024. doi:10.1016/j.str.2024.02.019. PMID 38537643. 
  5. ↑ 5.0 5.1 "PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing". Nature Immunology 19 (9): 942–953. September 2018. doi:10.1038/s41590-018-0179-y. PMID 30111894. 
  6. ↑ 6.0 6.1 "Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors". Nature Communications 12 (1). October 2021. doi:10.1038/s41467-021-26150-w. PMID 34620855. Bibcode: 2021NatCo..12.5874G. 
  7. ↑ "PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes" (in English). Cell 187 (24): 6820–6834.e24. November 2024. doi:10.1016/j.cell.2024.09.036. PMID 39423811. 
  8. ↑ "Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation". Immunity 57 (7): 1482–1496.e8. July 2024. doi:10.1016/j.immuni.2024.04.010. PMID 38697119. 
  9. ↑ 9.0 9.1 "Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus". Nature. September 2025. doi:10.1038/s41586-025-09513-x. PMID 40931063. 
  10. ↑ "rs2841277 (PLD4) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis". Oncotarget 8 (38): 64180–64190. September 2017. doi:10.18632/oncotarget.19419. PMID 28969061. 
  11. ↑ "PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population". Arthritis and Rheumatism 65 (2): 472–480. February 2013. doi:10.1002/art.37777. PMID 23124809. 
  12. ↑ "Disease in the Pld4thss/thss Model of Murine Lupus Requires TLR9". ImmunoHorizons 7 (8): 577–586. August 2023. doi:10.4049/immunohorizons.2300058. PMID 37555846. 
  13. ↑ Jung, Simone; Pausch, Hubert; Langenmayer, Martin C.; Schwarzenbacher, Hermann; Majzoub-Altweck, Monir; Gollnick, Nicole S.; Fries, Ruedi (2014-07-22). "A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle". BMC Genomics 15 (1): 623. doi:10.1186/1471-2164-15-623. ISSN 1471-2164. PMID 25052073. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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