ID   NSMA3_MOUSE             Reviewed;         823 AA.
AC   Q6ZPR5; Q3TPE0; Q3TPP1; Q8CBJ5; Q8CD12; Q8CD83; Q8R0J3; Q9CX74;
DT   23-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 2.
DT   02-SEP-2026, entry version 138.
DE   RecName: Full=Sphingomyelin phosphodiesterase 4;
DE            EC=3.1.4.12;
DE   AltName: Full=Neutral sphingomyelinase 3;
DE            Short=nSMase-3;
DE            Short=nSMase3 {ECO:0000303|PubMed:25180167};
DE   AltName: Full=Neutral sphingomyelinase III;
GN   Name=Smpd4; Synonyms=Kiaa1418;
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] (ISOFORM 1).
RC   TISSUE=Embryonic tail;
RX   PubMed=14621295; DOI=10.1093/dnares/10.4.167;
RA   Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA   Saga Y., Nagase T., Ohara O., Koga H.;
RT   "Prediction of the coding sequences of mouse homologues of KIAA gene: III.
RT   The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT   identified by screening of terminal sequences of cDNA clones randomly
RT   sampled from size-fractionated libraries.";
RL   DNA Res. 10:167-180(2003).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3; 4 AND 5).
RC   STRAIN=C57BL/6J; TISSUE=Cerebellum, Head, Testis, 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   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   STRAIN=FVB/N; TISSUE=Liver;
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   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-245, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brown adipose tissue, Kidney, 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   FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, ALTERNATIVE SPLICING,
RP   CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND COFACTOR.
RX   PubMed=25180167; DOI=10.1016/j.redox.2014.07.006;
RA   Moylan J.S., Smith J.D., Wolf Horrell E.M., McLean J.B., Deevska G.M.,
RA   Bonnell M.R., Nikolova-Karakashian M.N., Reid M.B.;
RT   "Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in
RT   skeletal muscle.";
RL   Redox Biol. 2:910-920(2014).
RN   [6]
RP   IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
RX   PubMed=31142202; DOI=10.1080/19491034.2019.1618175;
RA   Cheng L.C., Baboo S., Lindsay C., Brusman L., Martinez-Bartolome S.,
RA   Tapia O., Zhang X., Yates J.R. III, Gerace L.;
RT   "Identification of new transmembrane proteins concentrated at the nuclear
RT   envelope using organellar proteomics of mesenchymal cells.";
RL   Nucleus 10:126-143(2019).
CC   -!- FUNCTION: Catalyzes the hydrolysis of membrane sphingomyelin to form
CC       phosphorylcholine and ceramide (PubMed:25180167). It has a relevant
CC       role in the homeostasis of membrane sphingolipids, thereby influencing
CC       membrane integrity, and endoplasmic reticulum organization and
CC       function. May sensitize cells to DNA damage-induced apoptosis. In
CC       skeletal muscle, mediates TNF-stimulated oxidant production
CC       (PubMed:25180167). {ECO:0000250|UniProtKB:Q9NXE4,
CC       ECO:0000269|PubMed:25180167}.
CC   -!- CATALYTIC ACTIVITY: [Isoform 1]:
CC       Reaction=a sphingomyelin + H2O = phosphocholine + an N-acylsphing-4-
CC         enine + H(+); Xref=Rhea:RHEA:19253, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:17636, ChEBI:CHEBI:52639,
CC         ChEBI:CHEBI:295975; EC=3.1.4.12;
CC         Evidence={ECO:0000269|PubMed:25180167};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19254;
CC         Evidence={ECO:0000305|PubMed:25180167};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:25180167};
CC   -!- ACTIVITY REGULATION: Activated by phosphatidylserine and tumor necrosis
CC       factor (TNF) (PubMed:25180167). Inhibited by scyphostatin (By
CC       similarity). {ECO:0000250|UniProtKB:Q9NXE4,
CC       ECO:0000269|PubMed:25180167}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:25180167}; Single-pass membrane protein
CC       {ECO:0000255}. Golgi apparatus membrane {ECO:0000250|UniProtKB:Q9NXE4};
CC       Single-pass membrane protein {ECO:0000255}. Nucleus envelope
CC       {ECO:0000269|PubMed:31142202}. Cell membrane, sarcolemma
CC       {ECO:0000269|PubMed:25180167}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=5;
CC       Name=1; Synonyms=nSMase3a {ECO:0000303|PubMed:25180167};
CC         IsoId=Q6ZPR5-1; Sequence=Displayed;
CC       Name=2; Synonyms=nSMase3b {ECO:0000303|PubMed:25180167};
CC         IsoId=Q6ZPR5-2; Sequence=VSP_022485;
CC       Name=3;
CC         IsoId=Q6ZPR5-3; Sequence=VSP_022485, VSP_022486;
CC       Name=4;
CC         IsoId=Q6ZPR5-4; Sequence=VSP_022485, VSP_022487;
CC       Name=5;
CC         IsoId=Q6ZPR5-5; Sequence=VSP_022484, VSP_022485;
CC   -!- TISSUE SPECIFICITY: [Isoform 1]: Expressed in skeletal muscle (at
CC       protein level). {ECO:0000269|PubMed:25180167}.
CC   -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in skeletal muscle but a
CC       lower levels than isoform 1 (at protein level).
CC       {ECO:0000269|PubMed:25180167}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAC98164.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AK129354; BAC98164.1; ALT_INIT; mRNA.
DR   EMBL; AK019466; BAB31737.1; -; mRNA.
DR   EMBL; AK031029; BAC27221.1; -; mRNA.
DR   EMBL; AK031685; BAC27512.1; -; mRNA.
DR   EMBL; AK035892; BAC29229.1; -; mRNA.
DR   EMBL; AK164234; BAE37694.1; -; mRNA.
DR   EMBL; AK164456; BAE37796.1; -; mRNA.
DR   EMBL; BC026767; AAH26767.1; -; mRNA.
DR   CCDS; CCDS28009.1; -. [Q6ZPR5-1]
DR   CCDS; CCDS49779.1; -. [Q6ZPR5-3]
DR   CCDS; CCDS49780.1; -. [Q6ZPR5-4]
DR   CCDS; CCDS49781.1; -. [Q6ZPR5-2]
DR   RefSeq; NP_001158081.1; NM_001164609.2. [Q6ZPR5-4]
DR   RefSeq; NP_001158082.1; NM_001164610.2. [Q6ZPR5-2]
DR   RefSeq; NP_001158083.1; NM_001164611.2. [Q6ZPR5-3]
DR   RefSeq; NP_001390351.1; NM_001403422.1. [Q6ZPR5-2]
DR   RefSeq; NP_084221.2; NM_029945.4. [Q6ZPR5-1]
DR   RefSeq; XP_006522785.1; XM_006522722.3. [Q6ZPR5-1]
DR   RefSeq; XP_036016072.1; XM_036160179.1. [Q6ZPR5-1]
DR   AlphaFoldDB; Q6ZPR5; -.
DR   BioGRID; 218808; 3.
DR   FunCoup; Q6ZPR5; 3571.
DR   IntAct; Q6ZPR5; 2.
DR   STRING; 10090.ENSMUSP00000006053; -.
DR   SwissLipids; SLP:000001481; -. [Q6ZPR5-1]
DR   iPTMnet; Q6ZPR5; -.
DR   PhosphoSitePlus; Q6ZPR5; -.
DR   SwissPalm; Q6ZPR5; -.
DR   PaxDb; 10090-ENSMUSP00000006053; -.
DR   PeptideAtlas; Q6ZPR5; -.
DR   ProteomicsDB; 253024; -. [Q6ZPR5-1]
DR   ProteomicsDB; 253025; -. [Q6ZPR5-2]
DR   ProteomicsDB; 253026; -. [Q6ZPR5-3]
DR   ProteomicsDB; 253027; -. [Q6ZPR5-4]
DR   ProteomicsDB; 253028; -. [Q6ZPR5-5]
DR   Pumba; Q6ZPR5; -.
DR   Antibodypedia; 56085; 86 antibodies from 22 providers.
DR   DNASU; 77626; -.
DR   Ensembl; ENSMUST00000006053.13; ENSMUSP00000006053.7; ENSMUSG00000005899.15. [Q6ZPR5-1]
DR   Ensembl; ENSMUST00000090159.13; ENSMUSP00000087620.5; ENSMUSG00000005899.15. [Q6ZPR5-4]
DR   Ensembl; ENSMUST00000163476.10; ENSMUSP00000131867.2; ENSMUSG00000005899.15. [Q6ZPR5-2]
DR   Ensembl; ENSMUST00000165363.10; ENSMUSP00000130720.2; ENSMUSG00000005899.15. [Q6ZPR5-3]
DR   GeneID; 77626; -.
DR   KEGG; mmu:77626; -.
DR   UCSC; uc007yll.2; mouse. [Q6ZPR5-1]
DR   UCSC; uc007ylm.2; mouse. [Q6ZPR5-3]
DR   UCSC; uc007yln.2; mouse. [Q6ZPR5-4]
DR   UCSC; uc007ylo.2; mouse. [Q6ZPR5-2]
DR   UCSC; uc007ylp.2; mouse. [Q6ZPR5-5]
DR   AGR; MGI:1924876; -.
DR   CTD; 55627; -.
DR   MGI; MGI:1924876; Smpd4.
DR   VEuPathDB; HostDB:ENSMUSG00000005899; -.
DR   eggNOG; KOG4396; Eukaryota.
DR   GeneTree; ENSGT00390000006044; -.
DR   HOGENOM; CLU_012098_0_0_1; -.
DR   InParanoid; Q6ZPR5; -.
DR   OMA; EERGKIH; -.
DR   OrthoDB; 10251508at2759; -.
DR   PhylomeDB; Q6ZPR5; -.
DR   Reactome; R-MMU-9840310; Glycosphingolipid catabolism.
DR   BioGRID-ORCS; 77626; 4 hits in 79 CRISPR screens.
DR   PRO; PR:Q6ZPR5; -.
DR   Proteomes; UP000000589; Chromosome 16.
DR   RNAct; Q6ZPR5; protein.
DR   Bgee; ENSMUSG00000005899; Expressed in embryonic post-anal tail and 259 other cell types or tissues.
DR   ExpressionAtlas; Q6ZPR5; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; EXP:UniProtKB.
DR   GO; GO:0005794; C:Golgi apparatus; ISS:HGNC-UCL.
DR   GO; GO:0000139; C:Golgi membrane; ISS:UniProtKB.
DR   GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB.
DR   GO; GO:0005640; C:nuclear outer membrane; ISO:GO_Central.
DR   GO; GO:0042383; C:sarcolemma; IDA:UniProtKB.
DR   GO; GO:0005802; C:trans-Golgi network; ISS:HGNC-UCL.
DR   GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; IDA:UniProtKB.
DR   GO; GO:0050290; F:sphingomyelin phosphodiesterase D activity; ISS:HGNC-UCL.
DR   GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB.
DR   GO; GO:0046513; P:ceramide biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0007029; P:endoplasmic reticulum organization; ISO:GO_Central.
DR   GO; GO:0046475; P:glycerophospholipid catabolic process; ISO:GO_Central.
DR   GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR   GO; GO:0006685; P:sphingomyelin catabolic process; IDA:UniProtKB.
DR   InterPro; IPR024129; Sphingomy_SMPD4.
DR   PANTHER; PTHR12988; SPHINGOMYELIN PHOSPHODIESTERASE 4; 1.
DR   PANTHER; PTHR12988:SF6; SPHINGOMYELIN PHOSPHODIESTERASE 4; 1.
DR   Pfam; PF14724; mit_SMPDase; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cell membrane; Endoplasmic reticulum;
KW   Golgi apparatus; Hydrolase; Lipid metabolism; Magnesium; Membrane;
KW   Metal-binding; Nucleus; Phosphoprotein; Reference proteome; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..823
FT                   /note="Sphingomyelin phosphodiesterase 4"
FT                   /id="PRO_0000273164"
FT   TRANSMEM        776..796
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         130
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NXE4"
FT   MOD_RES         245
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         665
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NXE4"
FT   MOD_RES         749
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NXE4"
FT   VAR_SEQ         1..157
FT                   /note="Missing (in isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:16141072"
FT                   /id="VSP_022484"
FT   VAR_SEQ         288..316
FT                   /note="Missing (in isoform 2, isoform 3, isoform 4 and
FT                   isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:16141072"
FT                   /id="VSP_022485"
FT   VAR_SEQ         429
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:16141072"
FT                   /id="VSP_022486"
FT   VAR_SEQ         429
FT                   /note="W -> CLAPWSPYQHRGLR (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:16141072"
FT                   /id="VSP_022487"
FT   CONFLICT        7
FT                   /note="Q -> P (in Ref. 3; AAH26767)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        15
FT                   /note="S -> T (in Ref. 2; BAC27221)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        141
FT                   /note="P -> T (in Ref. 2; BAC27512)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        195
FT                   /note="F -> V (in Ref. 3; AAH26767)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        368
FT                   /note="V -> E (in Ref. 2; BAB31737)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        732
FT                   /note="F -> Y (in Ref. 2; BAC27221)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   823 AA;  93276 MW;  3C082D335608BA70 CRC64;
     MAFPHLQQPS FLLASLKADS INKPFAQRCQ DLVKVIEDFP AKELHAVFPW LVESIFGSLD
     GVLVGWNLRC LQGRVNPVEY STAMEFLDPS GPMMKLVYKL QAEDYNFDFP VSCLPGPVKA
     SIQENVLPDS PLYHNKVQFP PTGGLGLNLA LNPFEYYMFY FALSLISQKP MSMTLHVRTS
     DCAYFTLVDR YLSWFLPTEG SVPPPLCSSP GGSSPSPAPR TPAMPFASYG LHTSLLKRHI
     SHQTSVNADP ASHEIWRSET LLQVFVEMWL HHYSLEMYQK MQSPHAKLEV LHYRLTVSSA
     LHSPAQPSLQ ALHAYQESFT PTEEHVLVVR LLLKHLHAFA NSLKPDQASP SAHSHATSPL
     EEFKRAAVPR FVQQKLYVFL QHCFGHWPLD ATFRAVLEMW LSYLQPWRYA PEKQAQGSDP
     QPRCVSEKWA PFIQENLLMY TKLFVSFLNR ALRTDLVSPK NALMVFRVAK VFAQPNLAEM
     IQKGEQLFLE PELIIPHRQH RLFTVTTSFL SPWPPVVTDA SFKVKSHVYS LEGQDCKYTP
     MFGPEIRTLV LRLAQLITQA KQTAKSISDQ YVESPTGRSF LSWLTFGLTD TNSCYPANDL
     DEIGQDSIRK TDEYLEKALE YLRQIFRLSE AQLAQLTLAL GSARDENGKQ QLPDCIVGEE
     GLILTPLGRY QIINGLRRFE IEYQGDLELQ PIRSYEITSL VRALFRLSSA INRRFAGQMA
     ALCSRNDFLG SFCRYHLTEP ALSNRHLLSP VGRRQVTNPA RGPRLSLRFL GSYRTLLLLL
     MAFFVASLFC IGPLSCSLLL VLGYVLYAIA MTLLTERGKL HQL
//