PLD3
entrez
23646
canonical
uniprot
Q8IV08
canonical
ensembl
ENSG00000105223
resolver
ensp
ENSP00000348901
resolver
ensp
ENSP00000386293
resolver
ensp
ENSP00000386938
resolver
ensp
ENSP00000387022
resolver
ensp
ENSP00000387050
resolver
ensp
ENSP00000515107
resolver
ensp
ENSP00000515110
resolver
ensp
ENSP00000515111
resolver
ensp
ENSP00000515112
resolver
ensp
ENSP00000515113
resolver
ensp
ENSP00000515115
resolver
ensp
ENSP00000515116
resolver
ensp
ENSP00000515117
resolver
ensp
ENSP00000515118
resolver
ensp
ENSP00000515119
resolver
ensp
ENSP00000515120
resolver
ensp
ENSP00000515121
resolver
ensp
ENSP00000515122
resolver
ensp
ENSP00000515123
resolver
ensp
ENSP00000523135
resolver
ensp
ENSP00000523136
resolver
ensp
ENSP00000523137
resolver
ensp
ENSP00000523138
resolver
ensp
ENSP00000523139
resolver
ensp
ENSP00000523140
resolver
ensp
ENSP00000523141
resolver
ensp
ENSP00000523142
resolver
ensp
ENSP00000523143
resolver
ensp
ENSP00000523144
resolver
ensp
ENSP00000523145
resolver
ensp
ENSP00000523146
resolver
ensp
ENSP00000523147
resolver
ensp
ENSP00000523148
resolver
ensp
ENSP00000523149
resolver
ensp
ENSP00000523150
resolver
ensp
ENSP00000523151
resolver
ensp
ENSP00000523152
resolver
ensp
ENSP00000523153
resolver
ensp
ENSP00000523154
resolver
ensp
ENSP00000523155
resolver
ensp
ENSP00000523157
resolver
ensp
ENSP00000523159
resolver
ensp
ENSP00000523160
resolver
ensp
ENSP00000523161
resolver
ensp
ENSP00000523162
resolver
ensp
ENSP00000523163
resolver
ensp
ENSP00000594608
resolver
ensp
ENSP00000622109
resolver
ensp
ENSP00000622110
resolver
ensp
ENSP00000622112
resolver
ensp
ENSP00000622113
resolver
ensp
ENSP00000622115
resolver
enst
ENST00000356508
resolver
enst
ENST00000409281
resolver
enst
ENST00000409419
resolver
enst
ENST00000409587
resolver
enst
ENST00000409735
resolver
enst
ENST00000700616
resolver
enst
ENST00000700619
resolver
enst
ENST00000700620
resolver
enst
ENST00000700621
resolver
enst
ENST00000700623
resolver
enst
ENST00000700625
resolver
enst
ENST00000700626
resolver
enst
ENST00000700628
resolver
enst
ENST00000700630
resolver
enst
ENST00000700631
resolver
enst
ENST00000700632
resolver
enst
ENST00000700633
resolver
enst
ENST00000700634
resolver
enst
ENST00000700637
resolver
enst
ENST00000853076
resolver
enst
ENST00000853077
resolver
enst
ENST00000853078
resolver
enst
ENST00000853079
resolver
enst
ENST00000853080
resolver
enst
ENST00000853081
resolver
enst
ENST00000853082
resolver
enst
ENST00000853083
resolver
enst
ENST00000853084
resolver
enst
ENST00000853085
resolver
enst
ENST00000853086
resolver
enst
ENST00000853087
resolver
enst
ENST00000853088
resolver
enst
ENST00000853089
resolver
enst
ENST00000853090
resolver
enst
ENST00000853091
resolver
enst
ENST00000853092
resolver
enst
ENST00000853093
resolver
enst
ENST00000853094
resolver
enst
ENST00000853095
resolver
enst
ENST00000853096
resolver
enst
ENST00000853098
resolver
enst
ENST00000853100
resolver
enst
ENST00000853101
resolver
enst
ENST00000853102
resolver
enst
ENST00000853103
resolver
enst
ENST00000853104
resolver
enst
ENST00000924549
resolver
enst
ENST00000952050
resolver
enst
ENST00000952051
resolver
enst
ENST00000952053
resolver
enst
ENST00000952054
resolver
enst
ENST00000952056
resolver
genesymbol
PLD3
resolver
hgnc
HGNC:17158
resolver
uniprot
Q92853
resolver
uniprot
Q9BW87
resolver
uniprot_entry
PLD3_HUMAN
resolver
uniprot_sec
Q92853
resolver
uniprot_sec
Q9BW87
resolver
activity_regulation
ACTIVITY REGULATION: The exonuclease activity toward ssDNA substrate is Ca(2+) and Mg(2+)-independent, but it is inhibited by Fe(2+), Cu(2+) and to a lesser extent Zn(2+) ions. {ECO:0000269|PubMed:38537643}.
uniprot
proteins
amino_acid_sequence
MKPKLMYQELKVPAEEPANELPMNEIEAWKAAEKKARWVLLVLILAVVGFGALMTQLFLWEYGDLHLFGPNQRPAPCYDPCEAVLVESIPEGLDFPNASTGNPSTSQAWLGLLAGAHSSLDIASFYWTLTNNDTHTQEPSAQQGEEVLRQLQTLAPKGVNVRIAVSKPSGPQPQADLQALLQSGAQVRMVDMQKLTHGVLHTKFWVVDQTHFYLGSANMDWRSLTQVKELGVVMYNCSCLARDLTKIFEAYWFLGQAGSSIPSTWPRFYDTRYNQETPMEICLNGTPALAYLASAPPPLCPSGRTPDLKALLNVVDNARSFIYVAVMNYLPTLEFSHPHRFWPAIDDGLRRATYERGVKVRLLISCWGHSEPSMRAFLLSLAALRDNHTHSDIQVKLFVVPADEAQARIPYARVNHNKYMVTERATYIGTSNWSGNYFTETAGTSLLVTQNGRGGLRSQLEAIFLRDWDSPYSHDLDTSADSVGNACRLL
uniprot
proteins
disease_involvement
DISEASE: Spinocerebellar ataxia 46 (SCA46) [MIM:617770]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA46 is a slowly progressive, autosomal dominant form with onset in adulthood. {ECO:0000269|PubMed:29053796, ECO:0000269|PubMed:30312375, ECO:0000269|PubMed:38537643, ECO:0000269|PubMed:38697119, ECO:0000269|PubMed:39423811}. Note=The disease may be caused by variants affecting the gene represented in this entry. There is limited evidence for implication of PLD3 in SCA46. Knockout mice do not present signs of cerebellar degeneration or spinocerebellar ataxia at 9 months of age, challenging the interpretation of the suggested loss-of-function mechanism for PLD3 as the SCA46-causative gene. {ECO:0000269|PubMed:30312375}.; DISEASE: Note=Genetic variants in PLD3 have been suggested to be associated with an increased risk for Alzheimer disease (PubMed:24336208, PubMed:25832409). Further studies, however, did not support PLD3 involvement in this disease (PubMed:25832408, PubMed:25832410, PubMed:25832411, PubMed:25832413, PubMed:26411346). Futhermore, it is controversial whether PLD3 plays a role in amyloid precursor protein processing (APP) or not (PubMed:24336208). In a relevant Alzheimer's disease mouse model PLD3 deficiency does not affect APP metabolism or amyloid plaque burden (PubMed:28128235). However one study shown that PLD3 influences APP processing (PubMed:24336208). {ECO:0000269|PubMed:24336208, ECO:0000269|PubMed:25832408, ECO:0000269|PubMed:25832409, ECO:0000269|PubMed:25832410, ECO:0000269|PubMed:25832411, ECO:0000269|PubMed:25832413, ECO:0000269|PubMed:26411346, ECO:0000269|PubMed:28128235}.
uniprot
proteins
ec_number
2.3.1.-
uniprot
proteins
ec_number
3.1.16.1
uniprot
proteins
function
FUNCTION: Lysosomal 5'->3' exonuclease that functions in nucleic-acid sensing by immune cells. Hydrolyzes phosphodiester bond in single-stranded RNA and DNA molecules, with a higher efficiency for molecules with 5' uridine and guanosine residues. It can stall at certain sites and does not necessarily proceed to complete exonucleolytic degradation, thereby producing nucleoside 3'-monophosphates but also 5'-end 5'-hydroxy deoxyribonucleotide/ribonucleotide fragments (PubMed:30111894, PubMed:30312375, PubMed:34620855, PubMed:37994783, PubMed:38537643, PubMed:38697119). Through the processing of self and exogenous RNA and DNA molecules, provides molecular signals to toll-like receptors (TLRs) in innate immunity. Partially redundant with PLD4, it cooperates with the RNase T2/RNASET2 to generate 2',3'-cGMP and cytidine-rich RNA fragments that occupy the two TLR7 ligand-binding pockets, to trigger receptor activation and signaling (PubMed:34620855, PubMed:38697119). Degrades mitochondrial CpG-rich ssDNA fragments to prevent TLR9 activation and autoinflammatory response, but it can cleave viral RNA to generate ligands for TLR7 activation and initiate antiviral immune responses (PubMed:37225734). Can exert polynucleotide phosphatase activity toward 5'-phosphorylated single-stranded DNA substrates although at a slow rate (PubMed:38537643). Regulates the homeostasis and interorganellar communication of the endolysosomal system with an overall impact on cellular removal of dysfunctional organelles via autophagy as well as proper protein and lipid turnover (PubMed:28128235, PubMed:29368044, PubMed:37225734). May play a role in myotube formation in response to ER stress (PubMed:22428023). {ECO:0000269|PubMed:22428023, ECO:0000269|PubMed:28128235, ECO:0000269|PubMed:29368044, ECO:0000269|PubMed:30111894, ECO:0000269|PubMed:30312375, ECO:0000269|PubMed:34620855, ECO:0000269|PubMed:37225734, ECO:0000269|PubMed:37994783, ECO:0000269|PubMed:38537643, ECO:0000269|PubMed:38697119}.; FUNCTION: Can alternatively catalyze the transfer (transphosphatidylation) of a glycerol group between (S,R)-lysophosphatidylglycerol (LPG) and monoacylglycerol (MAG). The reaction is characterized by an R-to-S stereo-inversion which is essential for the resistance of the produced (S,S)-bis(monoacylglycero)phosphates (BMPs) to lysosomal degradation. The resulting BMPs, are phospholipids required for the formation of lysosomal intralumenal vesicles (ILVs) where lipid degradation can occur. {ECO:0000269|PubMed:39423811}.
uniprot
proteins
mass_dalton
54705
uniprot
proteins
mutagenesis
MUTAGEN 6; /note="M->R: No effect on protein maturation or trafficking to lysosomes. Decreases exonuclease activity toward mitochondrial CpG-rich ssDNA fragments resulting in mitochondrial DNA build-up in the endolysosomal compartment and increased mitophagy rate associated with accumulation of amyloid precursor protein-derived C-terminal fragments (APP-CTFs) in autophagosomes/autolysosomes."; /evidence="ECO:0000269|PubMed:37225734"; MUTAGEN 7; /note="Y->A: Slightly increases plasma membrane localization, does not affect delivery to lysosomes."; /evidence="ECO:0000269|PubMed:29386126"; MUTAGEN 163; /note="I->M: Tends to form aggregates. Decreases exonuclease activity toward ssDNA."; /evidence="ECO:0000269|PubMed:38537643"; MUTAGEN 201; /note="H->A: Loss of (S,S)-BMP synthase activity. No effect on protein expression or localization to lysosomes."; /evidence="ECO:0000269|PubMed:39423811"; MUTAGEN 201; /note="H->N: Decreases RNA binding; when associated with D-337 and N-416. Almost complete loss of RNA binding; when associated with D-340 and N-416."; /evidence="ECO:0000269|PubMed:38697119"; MUTAGEN 203; /note="K->A: Loss of (S,S)-BMP synthase activity. No effect on protein expression or localization to lysosomes."; /evidence="ECO:0000269|PubMed:39423811"; MUTAGEN 208; /note="D->A: Loss of (S,S)-BMP synthase activity. No effect on protein expression or localization to lysosomes."; /evidence="ECO:0000269|PubMed:39423811"; MUTAGEN 228; /note="K->R: Decreases exonuclease activity toward CpG-free or CpG-rich ssDNA substrates. Increases mitophagy rate. No effect on protein maturation or trafficking to lysosomes."; /evidence="ECO:0000269|PubMed:37225734"; MUTAGEN 236; /note="N->S: Increases exonuclease activity toward CpG-free ssDNA substrates. Slightly decreases exonuclease activity toward a CpG-rich ATP6 ssDNA sequence. Loss of exonuclease activity toward a CpG-rich ND4L ssDNA sequence. Increases mitophagy rate. No effect on protein maturation or trafficking to lysosomes."; /evidence="ECO:0000269|PubMed:37225734"; MUTAGEN 300; /note="C->S: No effect on proteolytical processing or localization to lysosomes."; /evidence="ECO:0000269|PubMed:37994783"; MUTAGEN 337; /note="H->D: Decreases exonuclease activity toward RNA. Decreases RNA binding; when associated with N-201 and N-416. Results in a 10-fold reduction of exonuclease activity toward RNA; when associated with N-339."; /evidence="ECO:0000269|PubMed:38697119"; MUTAGEN 339; /note="H->D: Results in a 10-fold reduction of exonuclease activity toward RNA; when associated with N-337."; /evidence="ECO:0000269|PubMed:38697119"; MUTAGEN 340; /note="R->D: Prevents dimerization resulting in decreased exonuclease activity toward RNA and CpG ssDNA substrates. Almost complete loss of RNA binding; when associated with N-201 and N-416."; /evidence="ECO:0000269|PubMed:38697119"; MUTAGEN 350; /note="R->A: Retained in the endoplasmic reticulum. Loss of exonuclease activity toward ssDNA; when associated with A-354; A-377 and A-380."; /evidence="ECO:0000269|PubMed:37994783"; MUTAGEN 354; /note="Y->A: Retained in the endoplasmic reticulum. Loss of exonuclease activity toward ssDNA; when associated with A-350, A-377 and A-380."; /evidence="ECO:0000269|PubMed:37994783"; MUTAGEN 356; /note="R->H: No effect on exonuclease activity toward ssDNA."; /evidence="ECO:0000269|PubMed:38537643"; MUTAGEN 377; /note="F->A: Retained in the endoplasmic reticulum. Loss of exonuclease activity toward ssDNA; when associated with A-350; A-354 and A-380."; /evidence="ECO:0000269|PubMed:37994783"; MUTAGEN 380; /note="S->A: Retained in the endoplasmic reticulum. Loss of exonuclease activity toward ssDNA; when associated with A-350; A-354 and A-377."; /evidence="ECO:0000269|PubMed:37994783"; MUTAGEN 388; /note="H->D: No effect on exonuclease activity toward RNA and CpG ssDNA."; /evidence="ECO:0000269|PubMed:38697119"; MUTAGEN 390; /note="H->D: No effect on exonuclease activity toward RNA and CpG ssDNA."; /evidence="ECO:0000269|PubMed:38697119"; MUTAGEN 410; /note="P->S: No effect on exonuclease activity toward ssDNA."; /evidence="ECO:0000269|PubMed:38537643"; MUTAGEN 411; /note="Y->A: Decreases exonuclease activity toward RNA and ssDNA."; /evidence="ECO:0000269|PubMed:38697119"; MUTAGEN 416; /note="H->A: Loss of (S,S)-BMP synthase activity. No effect on protein expression or localization to lysosomes."; /evidence="ECO:0000269|PubMed:39423811"; MUTAGEN 416; /note="H->N: Decreases RNA binding; when associated with N-201 and D-337. Almost complete loss of RNA binding; when associated with N-201 and D-340."; /evidence="ECO:0000269|PubMed:38697119"; MUTAGEN 418; /note="K->A: Loss of (S,S)-BMP synthase activity. Loss of exonuclease activity toward ssDNA. No effect on protein expression or localization to lysosomes."; /evidence="ECO:0000269|PubMed:39423811"; MUTAGEN 418; /note="K->R: Impairs myotube formation. Loss of exonuclease activity toward ssDNA. No effect on localization to lysosomes."; /evidence="ECO:0000269|PubMed:22428023, ECO:0000269|PubMed:28128235, ECO:0000269|PubMed:37994783"; MUTAGEN 423; /note="E->A: Loss of (S,S)-BMP synthase activity. No effect on protein expression or localization to lysosomes. Loss of exonuclease activity toward ssDNA."; /evidence="ECO:0000269|PubMed:37994783, ECO:0000269|PubMed:39423811"; MUTAGEN 423; /note="E->D: No effect on (S,S)-BMP synthase activity, protein expression or localization to lysosomes."; /evidence="ECO:0000269|PubMed:39423811"; MUTAGEN 432; /note="N->A: Loss of exonuclease activity toward ssDNA. No effect on protein localization to lysosomes."; /evidence="ECO:0000269|PubMed:37994783
uniprot
proteins
post_translational_modification
PTM: N-glycosylated. {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:29053796, ECO:0000269|PubMed:29386126, ECO:0000269|PubMed:37994783}.; PTM: Proteolytically processed to a soluble active form that is stable within endosomes and lysosomes. During transport through the secretory pathway becomes proteolysed by cysteine proteases, thereby releasing a stable soluble lysosomal lumenal polypeptide, whereas the transmembrane-bound fragment is rapidly degraded. Its transport route to lysosomes involves ubiquitination and the ESCRT complex. {ECO:0000269|PubMed:29386126, ECO:0000269|PubMed:37994783}.; PTM: Ubiquitinated at N-terminus. Ubiquitination mediates sorting into lysosomes. {ECO:0000269|PubMed:29386126}.
uniprot
proteins
protein_family
Phospholipase D family
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15794758
uniprot
proteins
pubmed
19159218
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
22428023
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24336208
uniprot
proteins
pubmed
25832408
uniprot
proteins
pubmed
25832409
uniprot
proteins
pubmed
25832410
uniprot
proteins
pubmed
25832411
uniprot
proteins
pubmed
25832413
uniprot
proteins
pubmed
25944712
uniprot
proteins
pubmed
26411346
uniprot
proteins
pubmed
28128235
uniprot
proteins
pubmed
29053796
uniprot
proteins
pubmed
29368044
uniprot
proteins
pubmed
29386126
uniprot
proteins
pubmed
30111894
uniprot
proteins
pubmed
30312375
uniprot
proteins
pubmed
34620855
uniprot
proteins
pubmed
37225734
uniprot
proteins
pubmed
37994783
uniprot
proteins
pubmed
38537643
uniprot
proteins
pubmed
38697119
uniprot
proteins
pubmed
39423811
uniprot
proteins
pubmed
9140189
uniprot
proteins
sequence_length
490
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Lysosome lumen {ECO:0000269|PubMed:29386126, ECO:0000269|PubMed:30312375, ECO:0000305|PubMed:39423811}. Early endosome membrane {ECO:0000269|PubMed:29386126}; Single-pass type II membrane protein {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:22428023}. Late endosome membrane {ECO:0000269|PubMed:29386126}; Single-pass type II membrane protein {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:22428023}. Endosome membrane {ECO:0000269|PubMed:29368044}; Single-pass type II membrane protein {ECO:0000269|PubMed:29368044}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:22428023}; Single-pass type II membrane protein {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:22428023}. Golgi apparatus membrane {ECO:0000269|PubMed:29368044}; Single-pass type II membrane protein {ECO:0000269|PubMed:29368044}. Note=Localizes to ER-associated vesicles in differentiating myotubes (PubMed:22428023). Sorted into intralumenal vesicles (ILVs) in lysosomes. The soluble form in lysosome arises by proteolytic processing of the membrane-bound form (PubMed:29386126). Colocalizes with APP in endosomes (PubMed:29368044). {ECO:0000269|PubMed:22428023, ECO:0000269|PubMed:29368044, ECO:0000269|PubMed:29386126}.
uniprot
proteins
transmembrane_region
TRANSMEM 39..59; /note="Helical; Signal-anchor for type II membrane protein"; /evidence="ECO:0000269|PubMed:22428023
uniprot
proteins