| PLD3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | PLD3, AD19, HU-K4, HUK4, phospholipase D family member 3, SCA46 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:615698;MGI:1333782;HomoloGene:7893;GeneCards:PLD3;OMA:PLD3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Phospholipase D3, also known asPLD3, is aprotein that in humans is encoded by thePLD3gene.[5][6] PLD3 belongs to thephospholipase Dsuperfamily because it contains the two HKD motifs common to members of the phospholipase D family, however, it has no known catalytic function similar toPLD1 orPLD2. PLD3 serves as a ssDNA 5' exonuclease in antigen presenting cells.[7] PLD3 is highly expressed in the brain in both humans and mice, and is mainly localized in theendoplasmic reticulum (ER) and thelysosome.
PLD3 may play a role in regulating the lysosomal system,myogenesis, late-stageneurogenesis, inhibitinginsulin signal transduction, andamyloid precursor protein (APP) processing. The involvement in PLD3 in the lysosomal system and in APP processing and theloss-of-function mutations in PLD3 are thought to be linked tolate-onset Alzheimer's disease (LOAD).[8][9] However, there are also studies that challenge the association between PLD3 and Alzheimer's disease (AD).[10][11][12][13][14]
How APP processing is affected by PLD3 during AD still remains unclear, and its role in the pathogenesis of AD is ambiguous.[14][15] PLD3 may contribute to the onset of AD by a mechanism other than by influencing APP metabolism, with one proposed mechanism suggesting that PLD3 contributes to the onset of AD by impairing the endosomal-lysosomal system.[14] In 2017, PLD3 was shown to have an association with another neurodegenerative disease,spinocerebellar ataxia.[16]
PLD3 was first characterized as a human homolog of theHindIII K4L protein in thevaccinia virus, having aDNA sequence 48.1% similar to the viral gene.[17] ThePLD3 gene in humans is located atchromosome 19q13.2, with a sequence comprising at least 15exons and isalternatively spliced at the low GC5' 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 thestop codon in exon 15.[18]
PLD3 is a 490 amino acid-longtype 2 transmembrane protein, unlike PLD1 and PLD2 which do not contain a transmembraneprotein domain in their protein structure.[18]
The cytosolicN-terminal of the protein faces towards the cytoplasm of the cell, and lacks consensus sites forN-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 theC-terminal domain.[21] The C-terminal domain contains sevenglycosylation sites along with aprenylation motif and two HXKXXXXD/E (HKD) motifs.[18] In PLD1 and PLD2, this is the catalytic domain oractive site of the protein, which is why PLD3 was assigned to thephospholipase Dsuperfamily.[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 itsmRNA.[18] The longer 2200base 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 matureneurons in the mammalianforebrain.[22] High expression of PLD3 is specifically seen in thehippocampus and thefrontal,temporal, andoccipital lobes in thecerebral cortex.[8][22] ThePLD3 gene is also found with high expression in the cerebellum.[16]
Subcellular localization of PLD3 is thought to primarily be in theendoplasmic reticulum (ER), as it has been shown to co-localize withprotein disulfide-isomerase, a protein known to be a marker for the ER.[18] PLD3 may also be localized in lysosomes, co-localizing with lysosomal markersLAMP1 andLAMP2 in lysosomes in separate studies.[14][23] PLD3 was identified as a protein ininsulin secretory granules derived frompancreatic beta cells.[24]
PLD3 is a member of thephospholipase Dprotein family, however, unlike phospholipasePLD1 andPLD2,[18] it serves as a 5'exonuclease that specifically degrade ssDNA in theendolysosome, 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 includingTLR9,TLR7 andcGAS-STING and triggersinflammation and elevated secretion ofcytokines.[7][25] It is shown thatmitochondrial DNA (mtDNA) is the major physiological substrate for PLD3 to degrade.[26]
PLD3 may play some role in influencing protein processing through thelysosome as well as a regulatory role in lysosomal morphology.[14] Some studies suggest that PLD3 is involved inamyloid precursor protein (APP) processing and regulatingamyloid beta (Aβ) levels.[8] Overexpression ofwildtype 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 sensingoxidative stress, such that suppressing the PLD3 gene withshort hairpin RNA increased the viability of cells exposed to oxidative stress.[27]
Increased PLD3 expression was shown to increase myotube formation in differentiated mousemyoblastsin vitro, andER 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 inmyogenesis, although its exact mechanism of action remains unknown.[20] Overexpression of PLD3 in mouse myoblastsin vitro may inhibitAktphosphorylation and blocksignal transduction duringinsulin signalling.[28] PLD3 may be involved in the later stages ofneurogenesis, contributing to processes associated withneurotransmission, 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 ofhematopoietic 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 thehuman 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 myoblastsin vitro.[28]
Mutations in PLD3 have been studied for their potential role in the pathogenesis oflate-onset Alzheimer's disease (LOAD).[8]
In 2013, Cruchagaet al. found that a particular rare coding variant ormissense mutation in PLD3 (Val232Met) doubled the risk for Alzheimer's disease among cases and controls of European and African-American descent.[8] PLD3 mRNA and protein expression was reduced in AD brains compared with non-AD brains in regions that PLD3 is normally found with high expression, and another study also found that PLD3 accumulates on neuritic plaques in AD brains.[8][30] A common PLD3single nucleotide polymorphism (SNP) was also found to have an association with Aβ pathology among normal, healthy individuals, suggesting that common PLD3 variants may also be involved in the pathogenesis of AD.[31] Ameta-analysis conducted in 2015 concluded that the Val232Met PLD3 variant has a modest effect on increasing AD risk.[9]
However, the findings from Cruchagaet al. could not be replicated in follow-up studies on the role of PLD3 in both familial and non-familial, sporadic Alzheimer's disease in Western population samples.[10][11][12] The Val232Met PLD3 mutant was also not identified in a sample of AD patients and healthy control subjects from mainland China, suggesting that this particular PLD3 mutant may not significantly affect AD risk in the mainland Chinese population.[13] A study showed that while there is an excess of PLD3 variants in LOAD, none of the variants described by Cruchagaet al. drive the association between PLD3 and LOAD in a European cohort, including the Val232Met variant.[32] This study along with an additional study also demonstrated that these rare coding variants of PLD3 were not observed in early-onset AD (EOAD) in a European cohort, suggesting that PLD3 may not have a role in EOAD.[32][33]
The underlying mechanisms on how mutations in PLD3 affects APP processing in AD remains unclear.[15] Results from the study by Cruchagaet al. indicated that PLD3loss-of-function increases risk for Alzheimer's disease by affecting APP processing.[8] The involvement of PLD3 in APP processing was challenged in a recent study which showed that a PLD3 loss-of-function does not significantly affect the burden ofamyloid plaques on AD development in mice.[14] PLD3 loss-of-function in this study did, however, change the morphology of the lysosomal system in neurons, indicating that PLD3 loss-of-function may still be involved in the pathophysiology of AD through some other mechanism such as by contributing to the impairment of the endosomal-lysosomal system that occurs during AD.[34][35]
In 2017, thePLD3 gene was identified as one of the novel genes linked tospinocerebellar ataxia, another neurodegenerative genetic disease.[16]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
