PLD4_MOUSE
ID PLD4_MOUSE Reviewed; 503 AA.
AC Q8BG07; Q3TD59; Q3UA19; Q6PDR0; Q8BR69;
DT 20-MAR-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 140.
DE RecName: Full=5'-3' exonuclease PLD4 {ECO:0000305};
DE EC=3.1.16.1 {ECO:0000269|PubMed:30111894};
DE AltName: Full=Choline phosphatase 4;
DE AltName: Full=Phosphatidylcholine-hydrolyzing phospholipase D4;
DE AltName: Full=Phospholipase D4;
DE Short=PLD 4;
GN Name=Pld4;
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 [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J, and NOD;
RC TISSUE=Bone marrow, Corpora quadrigemina, Hypothalamus, and Thymus;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=FVB/N-3; TISSUE=Mammary tumor;
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 [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung, and Spleen;
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 [4]
RP DEVELOPMENTAL STAGE, SUBCELLULAR LOCATION, GLYCOSYLATION, LACK OF
RP PHOSPHOLIPASE ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=21085684; DOI=10.1371/journal.pone.0013932;
RA Yoshikawa F., Banno Y., Otani Y., Yamaguchi Y., Nagakura-Takagi Y.,
RA Morita N., Sato Y., Saruta C., Nishibe H., Sadakata T., Shinoda Y.,
RA Hayashi K., Mishima Y., Baba H., Furuichi T.;
RT "Phospholipase D family member 4, a transmembrane glycoprotein with no
RT phospholipase D activity, expression in spleen and early postnatal
RT microglia.";
RL PLoS ONE 5:E13932-E13932(2010).
RN [5]
RP SUBCELLULAR LOCATION, INDUCTION, FUNCTION, AND GLYCOSYLATION.
RX PubMed=22102906; DOI=10.1371/journal.pone.0027544;
RA Otani Y., Yamaguchi Y., Sato Y., Furuichi T., Ikenaka K., Kitani H.,
RA Baba H.;
RT "PLD4 is involved in phagocytosis of microglia: expression and localization
RT changes of PLD4 are correlated with activation state of microglia.";
RL PLoS ONE 6:E27544-E27544(2011).
RN [6]
RP DISRUPTION PHENOTYPE, FUNCTION, AND CATALYTIC ACTIVITY.
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
CC (PubMed:30111894). Involved in phagocytosis of activated microglia
CC (PubMed:22102906). {ECO:0000269|PubMed:22102906,
CC 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 pH 5.5-5. {ECO:0000269|PubMed:30111894};
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:21085684}; Single-pass type II membrane protein
CC {ECO:0000305|PubMed:21085684}. Golgi apparatus, trans-Golgi network
CC membrane {ECO:0000269|PubMed:21085684}; Single-pass type II membrane
CC protein {ECO:0000305|PubMed:21085684}. Nucleus
CC {ECO:0000269|PubMed:22102906}. Early endosome
CC {ECO:0000305|PubMed:22102906}. Cytoplasmic vesicle, phagosome
CC {ECO:0000269|PubMed:22102906}. Note=Activation of microglia induces
CC translocation of PLD4 from the nucleus to the phagosomes.
CC {ECO:0000269|PubMed:22102906}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8BG07-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8BG07-2; Sequence=VSP_023630;
CC -!- TISSUE SPECIFICITY: Enriched in the white matter of early postnatal
CC brains, as well as in splenic marginal zone cells (PubMed:21085684).
CC Highly expressed in dendritic cells (DCs) and other myeloid cells, with
CC lower expression in B cell (PubMed:30111894).
CC {ECO:0000269|PubMed:21085684, ECO:0000269|PubMed:30111894}.
CC -!- DEVELOPMENTAL STAGE: First detected in cerebellum at postnatal day 0
CC (P0), increased with age and peaked at P7, and then rapidly decreased
CC to adult levels by P21. {ECO:0000269|PubMed:21085684}.
CC -!- INDUCTION: Up-regulated by lipopolysaccharide (LPS) stimulation in
CC microglia (PubMed:22102906). Increased expression in activated
CC microglia and in the demyelinating lesions of adult brain
CC (PubMed:22102906). {ECO:0000269|PubMed:22102906}.
CC -!- PTM: Highly N-glycosylated. {ECO:0000269|PubMed:21085684,
CC ECO:0000269|PubMed:22102906}.
CC -!- DISRUPTION PHENOTYPE: Deficient mice exhibit a phenotype of chronic
CC activation of the immune system, with splenomegaly marked by elevated
CC levels of interferon-gamma (IFN-gamma) (PubMed:30111894). PDL3 and PLD4
CC double-deficient mice are unable to survive beyond the age of 21 days
CC due to severe liver inflammation (PubMed:30111894). Livers from double-
CC knockout mice develop lethal hepatic autoinflammatory disease that
CC could be prevented by a single allele of either PDL3 or PLD4
CC (PubMed:30111894). {ECO:0000269|PubMed:30111894}.
CC -!- SIMILARITY: Belongs to the phospholipase D family. {ECO:0000305}.
CC -!- CAUTION: Exhibits no phospholipase activity, despite two HKD motifs.
CC {ECO:0000269|PubMed:30111894}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC32379.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK045459; BAC32379.1; ALT_FRAME; mRNA.
DR EMBL; AK079549; BAC37681.1; -; mRNA.
DR EMBL; AK079878; BAC37771.1; -; mRNA.
DR EMBL; AK151551; BAE30496.1; -; mRNA.
DR EMBL; AK170362; BAE41745.1; -; mRNA.
DR EMBL; BC058565; AAH58565.1; -; mRNA.
DR CCDS; CCDS26195.1; -. [Q8BG07-1]
DR RefSeq; NP_849242.1; NM_178911.4. [Q8BG07-1]
DR AlphaFoldDB; Q8BG07; -.
DR SMR; Q8BG07; -.
DR BioGRID; 222698; 1.
DR STRING; 10090.ENSMUSP00000067002; -.
DR GlyConnect; 2584; 4 N-Linked glycans (3 sites).
DR GlyGen; Q8BG07; 8 sites, 4 N-linked glycans (3 sites).
DR PhosphoSitePlus; Q8BG07; -.
DR EPD; Q8BG07; -.
DR jPOST; Q8BG07; -.
DR MaxQB; Q8BG07; -.
DR PaxDb; Q8BG07; -.
DR PeptideAtlas; Q8BG07; -.
DR PRIDE; Q8BG07; -.
DR ProteomicsDB; 289757; -. [Q8BG07-1]
DR ProteomicsDB; 289758; -. [Q8BG07-2]
DR Antibodypedia; 28277; 190 antibodies from 26 providers.
DR Ensembl; ENSMUST00000063888; ENSMUSP00000067002; ENSMUSG00000052160. [Q8BG07-1]
DR GeneID; 104759; -.
DR KEGG; mmu:104759; -.
DR UCSC; uc007pfc.1; mouse. [Q8BG07-1]
DR UCSC; uc007pfd.1; mouse. [Q8BG07-2]
DR CTD; 122618; -.
DR MGI; MGI:2144765; Pld4.
DR VEuPathDB; HostDB:ENSMUSG00000052160; -.
DR eggNOG; KOG3603; Eukaryota.
DR GeneTree; ENSGT00950000183059; -.
DR HOGENOM; CLU_027021_0_0_1; -.
DR InParanoid; Q8BG07; -.
DR OMA; TSCCRRP; -.
DR OrthoDB; 1057467at2759; -.
DR PhylomeDB; Q8BG07; -.
DR TreeFam; TF313378; -.
DR Reactome; R-MMU-1855204; Synthesis of IP3 and IP4 in the cytosol.
DR Reactome; R-MMU-2029485; Role of phospholipids in phagocytosis.
DR BioGRID-ORCS; 104759; 4 hits in 76 CRISPR screens.
DR ChiTaRS; Pld4; mouse.
DR PRO; PR:Q8BG07; -.
DR Proteomes; UP000000589; Chromosome 12.
DR RNAct; Q8BG07; protein.
DR Bgee; ENSMUSG00000052160; Expressed in spleen and 66 other tissues.
DR Genevisible; Q8BG07; MM.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0045335; C:phagocytic vesicle; IDA:UniProtKB.
DR GO; GO:0032588; C:trans-Golgi network membrane; IDA:UniProtKB.
DR GO; GO:0004630; F:phospholipase D activity; TAS:Reactome.
DR GO; GO:0045145; F:single-stranded DNA 5'-3' exodeoxyribonuclease activity; IMP:UniProtKB.
DR GO; GO:0051649; P:establishment of localization in cell; IMP:MGI.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IMP:MGI.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0006909; P:phagocytosis; IMP: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; 2.
DR Pfam; PF13918; PLDc_3; 1.
DR SMART; SM00155; PLDc; 2.
DR PROSITE; PS50035; PLD; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytoplasmic vesicle; Endoplasmic reticulum; Endosome;
KW Exonuclease; Glycoprotein; Golgi apparatus; Hydrolase; Immunity;
KW Inflammatory response; Innate immunity; Membrane; Nuclease; Nucleus;
KW Reference proteome; Repeat; Signal-anchor; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..503
FT /note="5'-3' exonuclease PLD4"
FT /id="PRO_0000280334"
FT TOPO_DOM 1..36
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:21085684"
FT TRANSMEM 37..57
FT /note="Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000305"
FT TOPO_DOM 58..503
FT /note="Lumenal"
FT /evidence="ECO:0000305|PubMed:21085684"
FT DOMAIN 207..234
FT /note="PLD phosphodiesterase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT DOMAIN 421..447
FT /note="PLD phosphodiesterase 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 212
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 214
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 219
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 426
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 428
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 433
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT CARBOHYD 89
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 148
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 169
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 247
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 279
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 415
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 425
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 442
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT VAR_SEQ 1..9
FT /note="MDKKKEHPE -> M (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_023630"
FT CONFLICT 223
FT /note="I -> V (in Ref. 2; AAH58565)"
FT /evidence="ECO:0000305"
FT CONFLICT 294
FT /note="F -> L (in Ref. 1; BAE41745)"
FT /evidence="ECO:0000305"
FT CONFLICT 450
FT /note="H -> Y (in Ref. 1; BAE41745)"
FT /evidence="ECO:0000305"
FT CONFLICT 452
FT /note="A -> G (in Ref. 1; BAC32379)"
FT /evidence="ECO:0000305"
FT CONFLICT 455
FT /note="G -> V (in Ref. 1; BAC32379)"
FT /evidence="ECO:0000305"
FT CONFLICT 483
FT /note="D -> G (in Ref. 1; BAC32379)"
FT /evidence="ECO:0000305"
FT CONFLICT 489
FT /note="A -> G (in Ref. 1; BAC32379)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 503 AA; 56154 MW; D72EB7DEBAC9598F CRC64;
MDKKKEHPEM RIPLQTAVEV SDWPCSTSHD PHSGLGMVLG MLAVLGLSSV TLILFLWQGA
TSFTSHRMFP EEVPSWSWET LKGDAEQQNN SCQLILVESI PEDLPFAAGS PTAQPLAQAW
LQLLDTARES VHIASYYWSL TGLDIGVNDS SSRQGEALLQ KFQQLLLRNI SVVVATHSPT
LAKTSTDLQV LAAHGAQIRQ VPMKQLTGGV LHSKFWVVDG RHIYVGSANM DWRSLTQVKE
LGAIIYNCSN LAQDLEKTFQ TYWVLGTPQA VLPKTWPRNF SSHINRFHPL RGPFDGVPTT
AYFSASPPSL CPHGRTRDLD AVLGVMEGAR QFIYVSVMEY FPTTRFTHHA RYWPVLDNAL
RAAALNKGVH VRLLVSCWFN TDPTMFAYLR SLQAFSNPSA GISVDVKVFI VPVGNHSNIP
FSRVNHSKFM VTDKTAYVGT SNWSEDYFSH TAGVGLIVSQ KTPRAQPGAT TVQEQLRQLF
ERDWSSHYAM DLDRQVPSQD CVW
