ID   DPP8_MOUSE              Reviewed;         892 AA.
AC   Q80YA7; Q9D4G6;
DT   07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2003, sequence version 1.
DT   24-JAN-2024, entry version 145.
DE   RecName: Full=Dipeptidyl peptidase 8 {ECO:0000303|PubMed:27820798};
DE            Short=DP8;
DE            EC=3.4.14.5 {ECO:0000250|UniProtKB:Q6V1X1};
DE   AltName: Full=Dipeptidyl peptidase VIII;
DE            Short=DPP VIII;
GN   Name=Dpp8 {ECO:0000303|PubMed:27820798, ECO:0000312|MGI:MGI:1921638};
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].
RC   STRAIN=C57BL/6J; TISSUE=Testis;
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].
RC   STRAIN=C57BL/6J; TISSUE=Brain;
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=Brain, Brown adipose tissue, Lung, 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   [4]
RP   FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=27820798; DOI=10.1038/nchembio.2229;
RA   Okondo M.C., Johnson D.C., Sridharan R., Go E.B., Chui A.J., Wang M.S.,
RA   Poplawski S.E., Wu W., Liu Y., Lai J.H., Sanford D.G., Arciprete M.O.,
RA   Golub T.R., Bachovchin W.W., Bachovchin D.A.;
RT   "DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and
RT   macrophage pyroptosis.";
RL   Nat. Chem. Biol. 13:46-53(2017).
RN   [5]
RP   FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=29396289; DOI=10.1016/j.chembiol.2017.12.013;
RA   Okondo M.C., Rao S.D., Taabazuing C.Y., Chui A.J., Poplawski S.E.,
RA   Johnson D.C., Bachovchin D.A.;
RT   "Inhibition of Dpp8/9 activates the Nlrp1b inflammasome.";
RL   Cell Chem. Biol. 25:262-267(2018).
CC   -!- FUNCTION: Dipeptidyl peptidase that cleaves off N-terminal dipeptides
CC       from proteins having a Pro or Ala residue at position 2 (By
CC       similarity). Acts as a key inhibitor of caspase-1-dependent monocyte
CC       and macrophage pyroptosis in resting cells by preventing activation of
CC       NLRP1 and CARD8 (PubMed:27820798, PubMed:29396289). Sequesters the
CC       cleaved C-terminal part of NLRP1 and CARD8, which respectively
CC       constitute the active part of the NLRP1 and CARD8 inflammasomes, in a
CC       ternary complex, thereby preventing their oligomerization and
CC       activation (By similarity). The dipeptidyl peptidase activity is
CC       required to suppress NLRP1 and CARD8; however, neither NLRP1 nor CARD8
CC       are bona fide substrates of DPP8, suggesting the existence of
CC       substrate(s) required for NLRP1 and CARD8 inhibition (By similarity).
CC       {ECO:0000250|UniProtKB:Q6V1X1, ECO:0000250|UniProtKB:Q86TI2,
CC       ECO:0000269|PubMed:27820798, ECO:0000269|PubMed:29396289}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a
CC         polypeptide, preferentially when Yaa is Pro, provided Zaa is neither
CC         Pro nor hydroxyproline.; EC=3.4.14.5;
CC         Evidence={ECO:0000250|UniProtKB:Q6V1X1};
CC   -!- ACTIVITY REGULATION: Inhibited by zinc (By similarity). Inhibited by
CC       the serine proteinase inhibitor 4-(2-aminoethyl)benzenesulphonyl
CC       fluoride (AEBSF), and by di-isopropylfluorophosphate (By similarity).
CC       Specifically inhibited by isoindoline derivatives (By similarity).
CC       Inhibited by Val-boroPro (Talabostat, PT-100), a non-selective
CC       inhibitor, which triggers pyroptosis in monocytes and macrophages
CC       (PubMed:27820798, PubMed:29396289). {ECO:0000250|UniProtKB:Q6V1X1,
CC       ECO:0000269|PubMed:27820798, ECO:0000269|PubMed:29396289}.
CC   -!- SUBUNIT: Homodimer (By similarity). Forms a ternary complex with NLRP1,
CC       composed of a DPP8 homodimer, one full-length NLRP1 protein, and one
CC       cleaved C-terminus of NLRP1 (NACHT, LRR and PYD domains-containing
CC       protein 1, C-terminus) (By similarity). Forms a ternary complex with
CC       CARD8, composed of a DPP8 homodimer, one full-length NLRP1 protein, and
CC       one cleaved C-terminus of CARD8 (Caspase recruitment domain-containing
CC       protein 8, C-terminus) (By similarity). In the ternary complex, only
CC       one subunit of the DPP8 homodimer is bound to NLRP1 or CARD8 (By
CC       similarity). {ECO:0000250|UniProtKB:Q6V1X1,
CC       ECO:0000250|UniProtKB:Q86TI2}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q6V1X1}.
CC   -!- SIMILARITY: Belongs to the peptidase S9B family. DPPIV subfamily.
CC       {ECO:0000305}.
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DR   EMBL; AK016546; BAB30295.2; -; mRNA.
DR   EMBL; BC043124; AAH43124.1; -; mRNA.
DR   EMBL; BC059222; AAH59222.1; -; mRNA.
DR   CCDS; CCDS23285.1; -.
DR   RefSeq; NP_083182.2; NM_028906.2.
DR   AlphaFoldDB; Q80YA7; -.
DR   SMR; Q80YA7; -.
DR   BioGRID; 216712; 7.
DR   STRING; 10090.ENSMUSP00000034960; -.
DR   ESTHER; mouse-dpp8; DPP4N_Peptidase_S9.
DR   MEROPS; S09.018; -.
DR   iPTMnet; Q80YA7; -.
DR   PhosphoSitePlus; Q80YA7; -.
DR   SwissPalm; Q80YA7; -.
DR   EPD; Q80YA7; -.
DR   MaxQB; Q80YA7; -.
DR   PaxDb; 10090-ENSMUSP00000034960; -.
DR   PeptideAtlas; Q80YA7; -.
DR   ProteomicsDB; 277601; -.
DR   Pumba; Q80YA7; -.
DR   Antibodypedia; 2238; 335 antibodies from 32 providers.
DR   DNASU; 74388; -.
DR   Ensembl; ENSMUST00000034960.14; ENSMUSP00000034960.7; ENSMUSG00000032393.16.
DR   Ensembl; ENSMUST00000167773.2; ENSMUSP00000126065.2; ENSMUSG00000032393.16.
DR   GeneID; 74388; -.
DR   KEGG; mmu:74388; -.
DR   UCSC; uc009qcq.1; mouse.
DR   AGR; MGI:1921638; -.
DR   CTD; 54878; -.
DR   MGI; MGI:1921638; Dpp8.
DR   VEuPathDB; HostDB:ENSMUSG00000032393; -.
DR   eggNOG; KOG2281; Eukaryota.
DR   GeneTree; ENSGT00940000160717; -.
DR   HOGENOM; CLU_006105_1_0_1; -.
DR   InParanoid; Q80YA7; -.
DR   OMA; AMQADKF; -.
DR   OrthoDB; 170111at2759; -.
DR   PhylomeDB; Q80YA7; -.
DR   TreeFam; TF313309; -.
DR   BioGRID-ORCS; 74388; 4 hits in 79 CRISPR screens.
DR   ChiTaRS; Dpp8; mouse.
DR   PRO; PR:Q80YA7; -.
DR   Proteomes; UP000000589; Chromosome 9.
DR   RNAct; Q80YA7; Protein.
DR   Bgee; ENSMUSG00000032393; Expressed in spermatocyte and 258 other cell types or tissues.
DR   ExpressionAtlas; Q80YA7; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR   GO; GO:0005829; C:cytosol; ISO:MGI.
DR   GO; GO:0004177; F:aminopeptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0008239; F:dipeptidyl-peptidase activity; ISS:UniProtKB.
DR   GO; GO:0008236; F:serine-type peptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0043069; P:negative regulation of programmed cell death; ISO:MGI.
DR   GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR   Gene3D; 3.40.50.1820; alpha/beta hydrolase; 1.
DR   Gene3D; 2.140.10.30; Dipeptidylpeptidase IV, N-terminal domain; 1.
DR   InterPro; IPR029058; AB_hydrolase.
DR   InterPro; IPR045785; Dpp_8/9_N.
DR   InterPro; IPR001375; Peptidase_S9.
DR   InterPro; IPR002469; Peptidase_S9B_N.
DR   PANTHER; PTHR11731:SF98; DIPEPTIDYL PEPTIDASE 8; 1.
DR   PANTHER; PTHR11731; PROTEASE FAMILY S9B,C DIPEPTIDYL-PEPTIDASE IV-RELATED; 1.
DR   Pfam; PF19520; Dpp_8_9_N; 1.
DR   Pfam; PF00930; DPPIV_N; 1.
DR   Pfam; PF00326; Peptidase_S9; 1.
DR   SUPFAM; SSF53474; alpha/beta-Hydrolases; 1.
DR   SUPFAM; SSF82171; DPP6 N-terminal domain-like; 1.
DR   Genevisible; Q80YA7; MM.
PE   1: Evidence at protein level;
KW   Aminopeptidase; Cytoplasm; Hydrolase; Protease; Reference proteome;
KW   Serine protease.
FT   CHAIN           1..892
FT                   /note="Dipeptidyl peptidase 8"
FT                   /id="PRO_0000122414"
FT   ACT_SITE        749
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250|UniProtKB:Q6V1X1"
FT   ACT_SITE        827
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250|UniProtKB:Q6V1X1"
FT   ACT_SITE        859
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250|UniProtKB:Q6V1X1"
FT   CONFLICT        87
FT                   /note="G -> R (in Ref. 1; BAB30295)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   892 AA;  102186 MW;  59081CD9792E03ED CRC64;
     MKIPSGRCNM AAAMETEQLG VEIFETAECE EGNGESQDRP KLEPFYVERY SWSQLKKLLA
     DTRKYHGYMM AKAPHDFMFV KRTDPDGPHS DRVYYLAMSG ENRENTLFYS EIPKTINRAA
     VLMLSWKPLL DLFQATLDYG MYSREEELLR ERKRIGTVGI AAYDYHPGSG TFLFQAGSGI
     YHIKDGGPHG FTQQPLRPNL VETSCPNIRM DPKLCPADPD WIAFIHSNDI WISNLVTREE
     RRITYVHNEL ANMEEDPRSA GVATFVLQEE FDRYSGYWWC PQAERTPSGG KILRILYEEN
     DESEVEIIHV TSPMLETRRA DSFRYPKTGT ANPKVTFKMS EIVVDAAGGI IDVIDKELVQ
     PFEILFEGVE YIARAGWTPE GKHAWSILLD RSQTHLQIVL ISPELFIPVE DDAMDRQRLI
     ESVPDSVTPL IIYEETTDIW INIHDIFHVF PQTHEDEIEF IFASECKTGF RHLYKITSIL
     KESKYKRSSG GLPAPSDFKC PIKEEITITS GEWEVLGRHG SNIWVDEARK LVYFEGTKDS
     PLEHHLYVTS YANPGEVVRL TDRGYSHSCC LSRHCDFFIS KYSNQKNPHC VSLYKLSSPE
     DDPVHKTKEF WATILDSAGP LPDYTPPEIF SFESTTGFTL YGMLYKPHDL QPGKKYPTVL
     FIYGGPQVQL VNNRFKGVKY FRLNTLASLG YVVVVIDNRG SCHRGLKFEG AFKYKMGQIE
     IDDQVEGLQY LASQYDFIDL DRVGIHGWSY GGYLSLMALM QRSDIFRVAI AGAPVTLWIF
     YDTGYTERYM GHPDQNEQGY YLGSVAMQAE KFPSEPNRLL LLHGFLDENV HFAHTSILLS
     FLVRAGKPYD LQIYPQERHS IRVPESGEHY ELHLLHYLQE NLGSRIAALK VI
//