PLD3_MOUSE
ID PLD3_MOUSE Reviewed; 488 AA.
AC O35405; Q3U5M5;
DT 20-MAR-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=5'-3' exonuclease PLD3;
DE EC=3.1.16.1 {ECO:0000269|PubMed:30111894};
DE AltName: Full=Choline phosphatase 3;
DE AltName: Full=Phosphatidylcholine-hydrolyzing phospholipase D3;
DE AltName: Full=Phospholipase D3;
DE Short=PLD 3;
DE AltName: Full=Schwannoma-associated protein 9;
DE Short=SAM-9 {ECO:0000303|PubMed:9813063};
GN Name=Pld3; Synonyms=Sam9;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND LACK OF PHOSPHOLIPASE
RP ACTIVITY.
RC STRAIN=C57BL/6 X DBA/2;
RX PubMed=9813063; DOI=10.1074/jbc.273.47.31494;
RA Pedersen K.M., Finsen B., Celis J.E., Jensen N.A.;
RT "Expression of a novel murine phospholipase D homolog coincides with late
RT neuronal development in the forebrain.";
RL J. Biol. Chem. 273:31494-31504(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Bone marrow;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP INDUCTION.
RX PubMed=22428023; DOI=10.1371/journal.pone.0033341;
RA Osisami M., Ali W., Frohman M.A.;
RT "A role for phospholipase D3 in myotube formation.";
RL PLoS ONE 7:E33341-E33341(2012).
RN [6]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, NOT INVOLVED IN APP METABOLISM,
RP AND DISRUPTION PHENOTYPE.
RX PubMed=28128235; DOI=10.1038/nature21030;
RA Fazzari P., Horre K., Arranz A.M., Frigerio C.S., Saito T., Saido T.C.,
RA De Strooper B.;
RT "PLD3 gene and processing of APP.";
RL Nature 541:E1-E2(2017).
RN [7]
RP DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND LACK OF PHOSPHOLIPASE D
RP ACTIVITY.
RX PubMed=30312375; DOI=10.1093/brain/awy258;
RA Gonzalez A.C., Stroobants S., Reisdorf P., Gavin A.L., Nemazee D.,
RA Schwudke D., D'Hooge R., Saftig P., Damme M.;
RT "PLD3 and spinocerebellar ataxia.";
RL Brain 141:E78-E78(2018).
RN [8]
RP GLYCOSYLATION.
RX PubMed=29386126; DOI=10.1016/j.celrep.2017.12.100;
RA Gonzalez A.C., Schweizer M., Jagdmann S., Bernreuther C., Reinheckel T.,
RA Saftig P., Damme M.;
RT "Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes.";
RL Cell Rep. 22:1040-1053(2018).
RN [9]
RP DISRUPTION PHENOTYPE, FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=30111894; DOI=10.1038/s41590-018-0179-y;
RA Gavin A.L., Huang D., Huber C., Maartensson A., Tardif V., Skog P.D.,
RA Blane T.R., Thinnes T.C., Osborn K., Chong H.S., Kargaran F., Kimm P.,
RA Zeitjian A., Sielski R.L., Briggs M., Schulz S.R., Zarpellon A.,
RA Cravatt B., Pang E.S., Teijaro J., de la Torre J.C., O'Keeffe M.,
RA Hochrein H., Damme M., Teyton L., Lawson B.R., Nemazee D.;
RT "PLD3 and PLD4 are single-stranded acid exonucleases that regulate
RT endosomal nucleic-acid sensing.";
RL Nat. Immunol. 19:942-953(2018).
CC -!- FUNCTION: 5'->3' DNA exonuclease which digests single-stranded DNA
CC (ssDNA) (PubMed:30111894). Regulates inflammatory cytokine responses
CC via the degradation of nucleic acids, by reducing the concentration of
CC ssDNA able to stimulate TLR9, a nucleotide-sensing receptor in
CC collaboration with PLD4 (PubMed:30111894). May be important in myotube
CC formation. Plays a role in lysosomal homeostasis. Involved in the
CC regulation of endosomal protein sorting (By similarity).
CC {ECO:0000250|UniProtKB:Q8IV08, ECO:0000269|PubMed:30111894}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Exonucleolytic cleavage in the 5'- to 3'-direction to yield
CC nucleoside 3'-phosphates.; EC=3.1.16.1;
CC Evidence={ECO:0000269|PubMed:30111894};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 5.5-5. {ECO:0000269|PubMed:30111894};
CC -!- SUBUNIT: Interacts with APP. {ECO:0000250|UniProtKB:Q8IV08}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q8IV08}; Single-pass type II membrane protein
CC {ECO:0000250|UniProtKB:Q8IV08}. Lysosome lumen
CC {ECO:0000250|UniProtKB:Q8IV08}. Early endosome membrane
CC {ECO:0000250|UniProtKB:Q8IV08}; Single-pass type II membrane protein
CC {ECO:0000250|UniProtKB:Q8IV08}. Late endosome membrane
CC {ECO:0000269|PubMed:28128235}; Single-pass type II membrane protein
CC {ECO:0000269|PubMed:28128235}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q8IV08}; Single-pass type II membrane protein
CC {ECO:0000250|UniProtKB:Q8IV08}. Endosome membrane
CC {ECO:0000250|UniProtKB:Q8IV08}; Single-pass type II membrane protein
CC {ECO:0000250|UniProtKB:Q8IV08}. Note=Localizes to ER-associated
CC vesicles in differentiating myotubes. The soluble form in lysosome
CC arises by proteolytic processing of the membrane-bound form.
CC {ECO:0000250|UniProtKB:Q8IV08}.
CC -!- TISSUE SPECIFICITY: Expressed at higher level in brain than in non-
CC nervous tissue. Expressed in mature neurons of the forebrain and
CC appears to be turned on at late stages of neurogenesis. Expressed
CC during late neuronal development in the forebrain (PubMed:9813063).
CC Expressed in the pyramidal neurons of the cortex and hippocampus
CC (PubMed:28128235). Low expression in the cerebellum (PubMed:30312375).
CC {ECO:0000269|PubMed:28128235, ECO:0000269|PubMed:30312375,
CC ECO:0000269|PubMed:9813063}.
CC -!- INDUCTION: Up-regulated during myoblast differentiation into myotubes.
CC {ECO:0000269|PubMed:22428023}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q8IV08}.
CC -!- PTM: Proteolytically processed to a soluble form that is stable within
CC endosomes and lysosomes. During transport through the secretory pathway
CC becomes proteolysed by cysteine proteases, thereby releasing a stable
CC soluble lysosomal lumenal polypeptide, whereas the transmembrane-bound
CC fragment is rapidly degraded. Its transport route to lysosomes involves
CC ubiquitination and the ESCRT complex. {ECO:0000250|UniProtKB:Q8IV08}.
CC -!- PTM: Ubiquitinated. Ubiquitination mediates sorting into lysosomes.
CC {ECO:0000250|UniProtKB:Q8IV08}.
CC -!- DISRUPTION PHENOTYPE: Deficient mice exhibit no altered phenotype
CC except a exaggerated response of macrophages to TLR9 (PubMed:30111894).
CC Morphology of PLD3-deficient brains does not reveal any major
CC abnormalities but an altered lysosomal structure (PubMed:29386126).
CC PDL3 and PLD4 double-deficient mice are unable to survive beyond the
CC age of 21 days due to severe liver inflammation (PubMed:30111894).
CC Livers from double-knockout mice develop lethal hepatic
CC autoinflammatory disease that could be prevented by a single allele of
CC either PDL3 or PLD4 (PubMed:30111894). {ECO:0000269|PubMed:29386126,
CC ECO:0000269|PubMed:30111894}.
CC -!- SIMILARITY: Belongs to the phospholipase D family. {ECO:0000305}.
CC -!- CAUTION: It was initially thought that PDL3 has phospholipase D
CC activity due to its HKD motifs. The second HKD motif contains Glu
CC instead of the canonical Asp. Its enzyme activity is therefore unsure.
CC Catalytic phospholipase D activity is still controversial
CC (PubMed:30312375, PubMed:9813063) (By similarity). Its closest homolog
CC PLD4, exhibits no phospholipase activity (By similarity).
CC {ECO:0000250|UniProtKB:Q8BG07, ECO:0000250|UniProtKB:Q8IV08,
CC ECO:0000269|PubMed:30312375, ECO:0000269|PubMed:9813063}.
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DR EMBL; AF026124; AAC73069.1; -; mRNA.
DR EMBL; AK153508; BAE32053.1; -; mRNA.
DR EMBL; BC076586; AAH76586.1; -; mRNA.
DR CCDS; CCDS21025.1; -.
DR RefSeq; NP_001304284.1; NM_001317355.1.
DR RefSeq; NP_035246.1; NM_011116.2.
DR RefSeq; XP_006539705.1; XM_006539642.2.
DR RefSeq; XP_006539706.1; XM_006539643.2.
DR AlphaFoldDB; O35405; -.
DR SMR; O35405; -.
DR BioGRID; 202241; 10.
DR STRING; 10090.ENSMUSP00000113820; -.
DR GlyConnect; 2583; 16 N-Linked glycans (3 sites).
DR GlyGen; O35405; 4 sites, 16 N-linked glycans (3 sites).
DR iPTMnet; O35405; -.
DR PhosphoSitePlus; O35405; -.
DR SwissPalm; O35405; -.
DR EPD; O35405; -.
DR jPOST; O35405; -.
DR MaxQB; O35405; -.
DR PaxDb; O35405; -.
DR PeptideAtlas; O35405; -.
DR PRIDE; O35405; -.
DR ProteomicsDB; 289928; -.
DR Antibodypedia; 2295; 140 antibodies from 23 providers.
DR DNASU; 18807; -.
DR Ensembl; ENSMUST00000117095; ENSMUSP00000113820; ENSMUSG00000003363.
DR Ensembl; ENSMUST00000117611; ENSMUSP00000112942; ENSMUSG00000003363.
DR GeneID; 18807; -.
DR KEGG; mmu:18807; -.
DR UCSC; uc009fwm.1; mouse.
DR CTD; 23646; -.
DR MGI; MGI:1333782; Pld3.
DR VEuPathDB; HostDB:ENSMUSG00000003363; -.
DR eggNOG; KOG3603; Eukaryota.
DR GeneTree; ENSGT00950000183059; -.
DR HOGENOM; CLU_027021_0_0_1; -.
DR InParanoid; O35405; -.
DR OMA; THFIPNT; -.
DR OrthoDB; 1057467at2759; -.
DR PhylomeDB; O35405; -.
DR TreeFam; TF313378; -.
DR Reactome; R-MMU-2029485; Role of phospholipids in phagocytosis.
DR BioGRID-ORCS; 18807; 1 hit in 75 CRISPR screens.
DR ChiTaRS; Pld3; mouse.
DR PRO; PR:O35405; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; O35405; protein.
DR Bgee; ENSMUSG00000003363; Expressed in dentate gyrus of hippocampal formation granule cell and 265 other tissues.
DR ExpressionAtlas; O35405; baseline and differential.
DR Genevisible; O35405; MM.
DR GO; GO:0031901; C:early endosome membrane; ISO:MGI.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISO:MGI.
DR GO; GO:0000139; C:Golgi membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB.
DR GO; GO:0043202; C:lysosomal lumen; ISO:MGI.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0004630; F:phospholipase D activity; ISS:MGI.
DR GO; GO:0045145; F:single-stranded DNA 5'-3' exodeoxyribonuclease activity; IDA:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0014902; P:myotube differentiation; ISO:MGI.
DR GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; IMP:UniProtKB.
DR InterPro; IPR032803; PLDc_3.
DR InterPro; IPR001736; PLipase_D/transphosphatidylase.
DR Pfam; PF00614; PLDc; 1.
DR Pfam; PF13918; PLDc_3; 1.
DR SMART; SM00155; PLDc; 2.
DR PROSITE; PS50035; PLD; 2.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Endosome; Exonuclease; Glycoprotein;
KW Golgi apparatus; Hydrolase; Immunity; Inflammatory response;
KW Innate immunity; Lysosome; Membrane; Nuclease; Reference proteome; Repeat;
KW Signal-anchor; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..488
FT /note="5'-3' exonuclease PLD3"
FT /id="PRO_0000280328"
FT TOPO_DOM 1..38
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8IV08"
FT TRANSMEM 39..59
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000250|UniProtKB:Q8IV08"
FT TOPO_DOM 60..488
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q8IV08"
FT DOMAIN 194..221
FT /note="PLD phosphodiesterase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT DOMAIN 409..435
FT /note="PLD phosphodiesterase 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 199
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 201
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 206
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT CARBOHYD 132
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CONFLICT 18
FT /note="A -> G (in Ref. 2; BAE32053)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 488 AA; 54389 MW; C7F0184EB09D7573 CRC64;
MKPKLMYQEL KVPVEEPAGE LPLNEIEAWK AAEKKARWVL LVLILAVVGF GALMTQLFLW
EYGDLHLFGP NQRPAPCYDP CEAVLVESIP EGLEFPNATT SNPSTSQAWL GLLAGAHSSL
DIASFYWTLT NNDTHTQEPS AQQGEEVLQQ LQALAPRGVK VRIAVSKPNG PLADLQSLLQ
SGAQVRMVDM QKLTHGVLHT KFWVVDQTHF YLGSANMDWR SLTQVKELGV VMYNCSCLAR
DLTKIFEAYW FLGQAGSSIP STWPRSFDTR YNQETPMEIC LNGTPALAYL ASAPPPLCPS
GRTPDLKALL NVVDSARSFI YIAVMNYLPT MEFSHPRRFW PAIDDGLRRA AYERGVKVRL
LISCWGHSDP SMRSFLLSLA ALHDNHTHSD IQVKLFVVPT DESQARIPYA RVNHNKYMVT
ERASYIGTSN WSGSYFTETA GTSLLVTQNG HGGLRSQLEA VFLRDWESPY SHDLDTSANS
VGNACRLL
