PLD3

Last updated
PLD3
Identifiers
Aliases PLD3 , AD19, HU-K4, HUK4, phospholipase D family member 3, SCA46
External IDs OMIM: 615698 MGI: 1333782 HomoloGene: 7893 GeneCards: PLD3
Orthologs
SpeciesHumanMouse
Entrez

23646

18807

Ensembl

ENSG00000105223

ENSMUSG00000003363

UniProt

Q8IV08

O35405

RefSeq (mRNA)

NM_001031696
NM_001291311
NM_012268

NM_011116
NM_001317355

RefSeq (protein)

NP_001026866
NP_001278240
NP_036400

NP_001304284
NP_035246

Location (UCSC) Chr 19: 40.35 – 40.38 Mb Chr 7: 27.23 – 27.25 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Phospholipase D3, also known as PLD3, is a protein that in humans is encoded by the PLD3 gene. [5] [6] PLD3 belongs to the phospholipase D superfamily because it contains the two HKD motifs common to members of the phospholipase D family, however, it has no known catalytic function similar to PLD1 or PLD2. 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 the endoplasmic reticulum (ER) and the lysosome.

Contents

PLD3 may play a role in regulating the lysosomal system, myogenesis, late-stage neurogenesis, inhibiting insulin signal transduction, and amyloid precursor protein (APP) processing. The involvement in PLD3 in the lysosomal system and in APP processing and the loss-of-function mutations in PLD3 are thought to be linked to late-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]

Genetics

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]

Structure

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-termina l 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]

Tissue and subcellular distribution

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]

Function

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]

Interactions

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]

Clinical significance

Alzheimer's disease

Mutations in PLD3 have been studied for their potential role in the pathogenesis of late-onset Alzheimer's disease (LOAD). [8]

In 2013, Cruchaga et al. found that a particular rare coding variant or missense 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 PLD3 single 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] A meta-analysis conducted in 2015 concluded that the Val232Met PLD3 variant has a modest effect on increasing AD risk. [9]

However, the findings from Cruchaga et 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 Cruchaga et 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 Cruchaga et al. indicated that PLD3 loss-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 of amyloid 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]

Spinocerebellar ataxia

In 2017, the PLD3 gene was identified as one of the novel genes linked to spinocerebellar ataxia, another neurodegenerative genetic disease. [16]

Related Research Articles

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Apolipoprotein E</span> Cholesterol-transporting protein most notably implicated in Alzheimers disease

Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">Beta-secretase 1</span> Enzyme

Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<span class="mw-page-title-main">Presenilin</span>

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.

<span class="mw-page-title-main">SORL1</span> Protein-coding gene in the species Homo sapiens

Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene.

<span class="mw-page-title-main">Granulin</span> Protein-coding gene in humans

Granulin is a protein that in humans is encoded by the GRN gene. Each granulin protein is cleaved from the precursor progranulin, a 593 amino-acid-long and 68.5 kDa protein. While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.

<span class="mw-page-title-main">APLP1</span> Protein-coding gene in the species Homo sapiens

Amyloid-like protein 1, also known as APLP1, is a protein that in humans is encoded by the APLP1 gene. APLP1 along with APLP2 are important modulators of glucose and insulin homeostasis.

<span class="mw-page-title-main">ABCA7</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family A member 7 is a protein that in humans is encoded by the ABCA7 gene.

<span class="mw-page-title-main">APBB2</span> Protein-coding gene in the species Homo sapiens

Amyloid beta A4 precursor protein-binding family B member 2 is a protein that in humans is encoded by the APBB2 gene.

<span class="mw-page-title-main">APBB3</span> Protein-coding gene in the species Homo sapiens

Amyloid beta A4 precursor protein-binding family B member 3 is a protein that in humans is encoded by the APBB3 gene.

<span class="mw-page-title-main">TMEM106B</span> Protein-coding gene in the species Homo sapiens

Transmembrane protein 106B is a protein that is encoded by the TMEM106B gene. It is found primarily within neurons and oligodendrocytes in the central nervous system with its subcellular location being in lysosomal membranes. TMEM106B helps facilitate important functions for maintaining a healthy lysosome, and therefore certain mutations and polymorphisms can lead to issues with proper lysosomal function. Lysosomes are in charge of clearing out mis-folded proteins and other debris, and thus, play an important role in neurodegenerative diseases that are driven by the accumulation of various mis-folded proteins and aggregates. Due to its impact on lysosomal function, TMEM106B has been investigated and found to be associated to multiple neurodegenerative diseases.

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<span class="mw-page-title-main">Rudolph E. Tanzi</span> American geneticist

Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, vice-chair of neurology, director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH).

Carlos Cruchaga is a human genomicist with expertise in multi-omics, informatics, and neurodegeneration, with a focus on Alzheimer's and Parkinson's Disease. He is a Professor of Psychiatry, Neurology and Genetics and Washington University School of Medicine. He is founding director of the Neurogenomics and Informatic (NGI) center at Washington University School of Medicine.

Alzheimer's disease (AD) is a complex neurodegenerative disease that affects millions of people across the globe. It is also a topic of interest in the East Asian population, especially as the burden of disease increases due to aging and population growth. The pathogenesis of AD between ethnic groups is different. However, prior studies in AD pathology have focused primarily on populations of European ancestry and may not give adequate insight on the genetic, clinical, and biological differences found in East Asians with AD. Gaps in knowledge regarding Alzheimer's disease in the East Asian population introduce serious barriers to screening, early prevention, diagnosis, treatment, and timely intervention.

References

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  6. ↑ Universal protein resource accession number Q8IV08 for "PLD3 - Phospholipase D3 - Homo sapiens" at UniProt.
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Further reading

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