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PLD4

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PLD4
Identifiers
AliasesPLD4, C14orf175, phospholipase D family member 4
External IDsOMIM: 618488; MGI: 2144765; HomoloGene: 16350; GeneCards: PLD4; OMA:PLD4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

122618

104759

Ensembl

ENSG00000166428

ENSMUSG00000052160

UniProt

Q96BZ4

Q8BG07

RefSeq (mRNA)

NM_001308174
NM_138790

NM_178911

RefSeq (protein)

NP_001295103
NP_620145

NP_849242

Location (UCSC)Chr 14: 104.92 – 104.94 MbChr 12: 112.73 – 112.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Phospholipase D family member 4 is an enzyme that in humans is encoded by the PLD4 gene.[5][6]

Tissue distribution

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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.[7]

Structure

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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. [8]

Function

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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.[9][10] 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.[8] 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.[11] 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. [9][10][12]

Clinical sigfnicance

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Genetic studies have associate PLD4 with several autoimmune diseases, such as SLE, rheumatoid arthritis and systemic sclerosis.[13][14][15] 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.[13][16][17]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000166428 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000052160 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: Phospholipase D family, member 4".
  6. ^ Universal protein resource accession number Q96BZ4 for "PLD4 - Phospholipase D4 - Homo sapiens" at UniProt.
  7. ^ "PLD4 - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2025-10-30.
  8. ^ a b Yuan M, Peng L, Huang D, Gavin A, Luan F, Tran J, et al. (June 2024). "Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4". Structure. 32 (6): 766–779.e7. doi:10.1016/j.str.2024.02.019. PMC 11162324. PMID 38537643.
  9. ^ a b Gavin AL, Huang D, Huber C, Mårtensson A, Tardif V, Skog PD, et al. (September 2018). "PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing". Nature Immunology. 19 (9): 942–953. doi:10.1038/s41590-018-0179-y. PMC 6105523. PMID 30111894.
  10. ^ a b Gavin AL, Huang D, Blane TR, Thinnes TC, Murakami Y, Fukui R, et al. (October 2021). "Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors". Nature Communications. 12 (1) 5874. Bibcode:2021NatCo..12.5874G. doi:10.1038/s41467-021-26150-w. PMC 8497607. PMID 34620855.
  11. ^ Singh S, Dransfeld UE, Ambaw YA, Lopez-Scarim J, Farese RV, Walther TC (November 2024). "PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes". Cell. 187 (24): 6820–6834.e24. doi:10.1016/j.cell.2024.09.036. PMC 12055030. PMID 39423811.
  12. ^ Bérouti M, Lammens K, Heiss M, Hansbauer L, Bauernfried S, Stöckl J, et al. (July 2024). "Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation". Immunity. 57 (7): 1482–1496.e8. doi:10.1016/j.immuni.2024.04.010. PMC 11470960. PMID 38697119.
  13. ^ a b Wang Q, Zhu H, Sun X, Zhang C, Ma S, Jin Y, et al. (September 2025). "Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus". Nature. doi:10.1038/s41586-025-09513-x. PMID 40931063.
  14. ^ Chen WC, Wang WC, Okada Y, Chang WP, Chou YH, Chang HH, et al. (September 2017). "rs2841277 (PLD4) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis". Oncotarget. 8 (38): 64180–64190. doi:10.18632/oncotarget.19419. PMC 5609993. PMID 28969061.
  15. ^ Terao C, Ohmura K, Kawaguchi Y, Nishimoto T, Kawasaki A, Takehara K, et al. (February 2013). "PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population". Arthritis and Rheumatism. 65 (2): 472–480. doi:10.1002/art.37777. PMID 23124809.
  16. ^ Gavin AL, Blane TR, Thinnes TC, Gerlt E, Marshak-Rothstein A, Huang D, et al. (August 2023). "Disease in the Pld4thss/thss Model of Murine Lupus Requires TLR9". ImmunoHorizons. 7 (8): 577–586. doi:10.4049/immunohorizons.2300058. PMC 10441812. PMID 37555846.
  17. ^ Jung S, Pausch H, Langenmayer MC, Schwarzenbacher H, Majzoub-Altweck M, Gollnick NS, et al. (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. PMC 4117962. PMID 25052073.

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

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