PLD4

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

PLD4
Identifiers
Aliases	PLD4, C14orf175, phospholipase D family member 4
External IDs	OMIM: 618488; MGI: 2144765; HomoloGene: 16350; GeneCards: PLD4; OMA:PLD4 - orthologs
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q32.33 Start 104,924,713 bp[1] End 104,937,761 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12|12 F1 Start 112,727,089 bp[2] End 112,735,424 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte monocyte C1 segment bone marrow cell testicle spleen substantia nigra appendix right hemisphere of cerebellum hypothalamus Top expressed in spleen white matter of cerebellum bone marrow granulocyte zone of skin white adipose tissue thymus lung jejunum ileum More reference expression data BioGPS n/a
Gene ontology Molecular function phospholipase D activity N-acylphosphatidylethanolamine-specific phospholipase D activity catalytic activity hydrolase activity phosphatidylinositol phospholipase C activity Cellular component integral component of membrane endoplasmic reticulum membrane membrane nucleus endoplasmic reticulum trans-Golgi network membrane phagocytic vesicle Biological process lipid catabolic process inositol phosphate metabolic process lipid metabolism hematopoietic progenitor cell differentiation phagocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 12: 112.73 – 112.74 Mb PubMed search [3] [4]
Wikidata
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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.^[7]

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. ^[8]

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.^[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

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]