PLD3

PLD3 was first characterized as a human homolog of the HindIII K4L protein in the vaccinia virus, having a DNA sequence 48.1% similar to the viral gene.[17] The PLD3 gene in humans is located at chromosome 19q13.2, with a sequence comprising at least 15 exons and is alternatively spliced at the low GC 5' UTR into 25 predicted transcripts.[18][19] Translation of the 490 amino acid-long PLD3 protein is initiated around exons 5 to 7, and ends at the stop codon in exon 15.[18]

PLD3 is a 490 amino acid-long type 2 transmembrane protein, unlike PLD1 and PLD2 which do not contain a transmembrane protein domain in their protein structure.[18]

The cytosolic N-terminal of the protein faces towards the cytoplasm of the cell, and lacks consensus sites for N-glycosylation.[18] The N-terminus is also predicted to contain a transmembrane domain.[20]

The bulk of the protein is located in the ER lumen, containing the C-terminal domain.[21] The C-terminal domain contains seven glycosylation sites along with a prenylation motif and two HXKXXXXD/E (HKD) motifs.[18] In PLD1 and PLD2, this is the catalytic domain or active site of the protein, which is why PLD3 was assigned to the phospholipase D superfamily.[18] However, PLD3 has no known catalytic activity and aside from presence of the HKD motifs, PLD3 has no structural commonalities with PLD1 or PLD2.[18]

Expression of PLD3 in tissues differs with the transcript size of its mRNA.[18] The longer 2200 base pair transcript is ubiquitously expressed in the body, exhibiting higher expression levels in the heart, skeletal muscle, and the brain.[18] Meanwhile, the shorter 1700 base pair transcript is found in abundance in the brain, but at low expression in non-nervous tissue.[18][22] PLD3 expression is especially pronounced in mature neurons in the mammalian forebrain.[22] High expression of PLD3 is specifically seen in the hippocampus and the frontal, temporal, and occipital lobes in the cerebral cortex.[8][22] The PLD3 gene is also found with high expression in the cerebellum.[16]

Subcellular localization of PLD3 is thought to primarily be in the endoplasmic reticulum (ER), as it has been shown to co-localize with protein disulfide-isomerase, a protein known to be a marker for the ER.[18] PLD3 may also be localized in lysosomes, co-localizing with lysosomal markers LAMP1 and LAMP2 in lysosomes in separate studies.[14][23] PLD3 was identified as a protein in insulin secretory granules derived from pancreatic beta cells.[24]

PLD3 is a member of the phospholipase D protein family, however, unlike phospholipase PLD1 and PLD2,[18] it serves as a 5' exonuclease that specifically degrade ssDNA in the endolysosome, which is similar to the function of PLD4. Both PLD3 and PLD4 are essential for the clearance of nucleic acid product in antigen presenting cells. Deletion of PLD3 and PLD4 leads to accumulation of ssDNA and RNA in the endosome, which activates various nucleic acid sensors including TLR9, TLR7 and cGAS-STING and triggers inflammation and elevated secretion of cytokines.[7][25] It is shown that mitochondrial DNA (mtDNA) is the major physiological substrate for PLD3 to degrade. [26]

PLD3 may play some role in influencing protein processing through the lysosome as well as a regulatory role in lysosomal morphology.[14] Some studies suggest that PLD3 is involved in amyloid precursor protein (APP) processing and regulating amyloid beta (Aβ) levels.[8] Overexpression of wildtype PLD3 is linked to a decrease in intracellular APP and extracellular Aβ isoforms Aβ40 and Aβ42, while a knockdown of PLD3 is linked to an increase in extracellular Aβ40 and Aβ42.[8] PLD3 was implied to be involved in sensing oxidative stress, such that suppressing the PLD3 gene with short hairpin RNA increased the viability of cells exposed to oxidative stress.[27]

Increased PLD3 expression was shown to increase myotube formation in differentiated mouse myoblasts in vitro, and ER stress which also increases myotube formation was also shown to increase PLD3 expression.[20] Decreasing PLD3 expression meanwhile decreases myotube formation.[20] These findings suggest a possible role of PLD3 in myogenesis, although its exact mechanism of action remains unknown.[20] Overexpression of PLD3 in mouse myoblasts in vitro may inhibit Akt phosphorylation and block signal transduction during insulin signalling.[28] PLD3 may be involved in the later stages of neurogenesis, contributing to processes associated with neurotransmission, target cell innervation, and neuronal survival.[22]

Elevated expression of PLD3 was found to be one of the consistent factors that contribute to the self-renewal activity of hematopoietic stem cell populations, suggesting a possible role of PLD3 in the mechanism behind the maintenance of durable, long-term self-renewing cell populations.[29]

The human progranulin protein (PGRN), encoded by the human granulin gene (GRN), is co-expressed with and interacts with PLD3 accumulated on neuritic plaques in AD brains.[30] PLD3 may interact with APP and amyloid beta, as some studies indicate that PLD3 is involved with APP processing and regulating Aβ levels.[8] PLD3 may also interact with Akt and insulin in myoblasts in vitro.[28]

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