ID SLPI_MOUSE Reviewed; 131 AA. AC P97430; O09081; O09082; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1997, sequence version 1. DT 24-JAN-2024, entry version 169. DE RecName: Full=Antileukoproteinase; DE Short=ALP; DE AltName: Full=Secretory leukocyte protease inhibitor {ECO:0000303|PubMed:9039268}; DE Flags: Precursor; GN Name=Slpi; 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], FUNCTION, INDUCTION BY BACTERIAL RP LIPOPOLYSACCHARIDE, AND TISSUE SPECIFICITY. RX PubMed=9039268; DOI=10.1016/s0092-8674(00)81880-2; RA Jin F.-Y., Nathan C.F., Radzioch D., Ding A.; RT "Secretory leukocyte protease inhibitor: a macrophage product induced by RT and antagonistic to bacterial lipopolysaccharide."; RL Cell 88:417-426(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 26-51, FUNCTION, RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=9126337; DOI=10.1006/bbrc.1997.6358; RA Zitnik R.J., Zhang J., Kashem M.A., Kohno T., Lyons D.E., Wright C.D., RA Rosen E., Goldberg I., Hayday A.C.; RT "The cloning and characterization of a murine secretory leukocyte protease RT inhibitor cDNA."; RL Biochem. Biophys. Res. Commun. 232:687-697(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND INDUCTION BY PNEUMONIA. RC STRAIN=C57BL/6 X CBA; TISSUE=Lung; RX PubMed=9351627; DOI=10.1164/ajrccm.156.4.9701075; RA Abe T., Tominaga Y., Kikuchi T., Watanabe A., Satoh K., Watanabe Y., RA Nukiwa T.; RT "Bacterial pneumonia causes augmented expression of the secretory RT leukoprotease inhibitor gene in the murine lung."; RL Am. J. Respir. Crit. Care Med. 156:1235-1240(1997). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Mammary gland; 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 [5] RP DISRUPTION PHENOTYPE, FUNCTION, AND INDUCTION BY WOUNDING. RX PubMed=11017147; DOI=10.1038/80489; RA Ashcroft G.S., Lei K., Jin W., Longenecker G., Kulkarni A.B., RA Greenwell-Wild T., Hale-Donze H., McGrady G., Song X.Y., Wahl S.M.; RT "Secretory leukocyte protease inhibitor mediates non-redundant functions RT necessary for normal wound healing."; RL Nat. Med. 6:1147-1153(2000). RN [6] RP INTERACTION WITH GRN. RX PubMed=12526812; DOI=10.1016/s0092-8674(02)01141-8; RA Zhu J., Nathan C., Jin W., Sim D., Ashcroft G.S., Wahl S.M., Lacomis L., RA Erdjument-Bromage H., Tempst P., Wright C.D., Ding A.; RT "Conversion of proepithelin to epithelins: roles of SLPI and elastase in RT host defense and wound repair."; RL Cell 111:867-878(2002). RN [7] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=12615907; DOI=10.1084/jem.20021824; RA Nakamura A., Mori Y., Hagiwara K., Suzuki T., Sakakibara T., Kikuchi T., RA Igarashi T., Ebina M., Abe T., Miyazaki J., Takai T., Nukiwa T.; RT "Increased susceptibility to LPS-induced endotoxin shock in secretory RT leukoprotease inhibitor (SLPI)-deficient mice."; RL J. Exp. Med. 197:669-674(2003). RN [8] RP DISRUPTION PHENOTYPE, FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, RP AND MUTAGENESIS OF 39-LYS-LYS-40; LYS-92 AND ARG-96. RX PubMed=18322212; DOI=10.4049/jimmunol.180.6.4032; RA Nishimura J., Saiga H., Sato S., Okuyama M., Kayama H., Kuwata H., RA Matsumoto S., Nishida T., Sawa Y., Akira S., Yoshikai Y., Yamamoto M., RA Takeda K.; RT "Potent antimycobacterial activity of mouse secretory leukocyte protease RT inhibitor."; RL J. Immunol. 180:4032-4039(2008). RN [9] RP DISRUPTION PHENOTYPE, FUNCTION, AND INDUCTION. RX PubMed=25030421; DOI=10.1189/jlb.4a0612-295rr; RA McCartney-Francis N., Jin W., Belkaid Y., McGrady G., Wahl S.M.; RT "Aberrant host defense against Leishmania major in the absence of SLPI."; RL J. Leukoc. Biol. 96:917-929(2014). CC -!- FUNCTION: Acid-stable proteinase inhibitor with strong affinities for CC trypsin, chymotrypsin, elastase, and cathepsin G (PubMed:9126337). CC Modulates the innate immune response after bacterial infection CC (PubMed:12615907). Contributes to regulate the inflammatory and immune CC responses to the intracellular parasite L.major (PubMed:25030421). CC Down-regulates responses to bacterial lipopolysaccharide (LPS) CC (PubMed:9039268, PubMed:12615907, PubMed:25030421). Plays a role in CC regulating the activation of NF-kappa-B and inflammatory responses CC (PubMed:11017147, PubMed:12615907). Has antimicrobial activity against CC mycobacteria, but not against salmonella (PubMed:18322212). Contributes CC to normal resistance against infection by M.tuberculosis CC (PubMed:18322212). Required for normal resistance to L.major CC (PubMed:25030421). Required for normal wound healing, probably by CC preventing tissue damage by limiting protease activity CC (PubMed:11017147, PubMed:25030421). Together with ELANE, required for CC normal differentiation and proliferation of bone marrow myeloid cells CC (By similarity). {ECO:0000250|UniProtKB:P03973, CC ECO:0000269|PubMed:11017147, ECO:0000269|PubMed:12615907, CC ECO:0000269|PubMed:18322212, ECO:0000269|PubMed:25030421, CC ECO:0000269|PubMed:9039268, ECO:0000269|PubMed:9126337, CC ECO:0000269|PubMed:9351627, ECO:0000305}. CC -!- SUBUNIT: Interacts with GRN; interaction protects progranulin from CC proteolysis. {ECO:0000269|PubMed:12526812}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:18322212, CC ECO:0000269|PubMed:9126337}. CC -!- TISSUE SPECIFICITY: Detected in bronchial epithelial cells CC (PubMed:18322212). Detected in bronchoalveolar fluid after infection CC with M.tuberculosis (at protein level) (PubMed:18322212). Highest CC expression in lung, spleen, intestine and epididymis with lower levels CC in liver and seminal vesicle. No expression in brain, heart, kidney and CC muscle. {ECO:0000269|PubMed:18322212, ECO:0000269|PubMed:9039268, CC ECO:0000269|PubMed:9126337, ECO:0000269|PubMed:9351627}. CC -!- INDUCTION: Up-regulated by bacterial lipopolysaccharide CC (PubMed:9039268, PubMed:25030421). Up-regulated in lung after infection CC with M.tuberculosis (PubMed:18322212). Down-regulated by IFNG CC (PubMed:9039268). Up-regulated in lung in response to bacterial CC pneumonia (PubMed:9351627). Up-regulated in macrophages after exposure CC to L.major (PubMed:25030421). Not up-regulated in spleen in response to CC bacterial pneumonia (PubMed:9351627). Up-regulated in wounded skin CC (PubMed:11017147). {ECO:0000269|PubMed:11017147, CC ECO:0000269|PubMed:18322212, ECO:0000269|PubMed:25030421, CC ECO:0000269|PubMed:9039268, ECO:0000269|PubMed:9351627}. CC -!- DISRUPTION PHENOTYPE: Mutant mice show delayed epithelial wound healing CC and an increased inflammatory response at the site of wounding, CC possibly due to increased elastase activity (PubMed:11017147, CC PubMed:25030421). Mutant mice show an increased tendency to die from CC toxic shock after exposure to bacterial lipopolysaccharide (LPS) CC (PubMed:12615907). Mutant mice are highly susceptible to CC M.tuberculosis; all die within 50 days after infection CC (PubMed:18322212). Mutant mice are highly susceptible infection by CC L.major. Contrary to what is observed with wild-type, the parasites are CC not restricted to the initial site of infection, but spread to spleen, CC liver and bone morrow. The skin lesions at the initial site of CC infection do not heal normally, but become bigger over time, in CC parallel with the spread of the parasites. The inflammatory response at CC the site of infection is more intense and persists longer than normal. CC Increased protease activity is observed in these lesions and may be the CC cause of the extensive tissue damage and necrosis (PubMed:25030421). CC {ECO:0000269|PubMed:11017147, ECO:0000269|PubMed:12615907, CC ECO:0000269|PubMed:18322212, ECO:0000269|PubMed:25030421}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U73004; AAC53047.1; -; mRNA. DR EMBL; U88093; AAC53140.1; -; mRNA. DR EMBL; U94341; AAC53394.1; -; mRNA. DR EMBL; BC028509; AAH28509.1; -; mRNA. DR CCDS; CCDS17033.1; -. DR RefSeq; NP_035544.1; NM_011414.3. DR AlphaFoldDB; P97430; -. DR SMR; P97430; -. DR BioGRID; 203333; 1. DR STRING; 10090.ENSMUSP00000104992; -. DR MEROPS; I17.001; -. DR PhosphoSitePlus; P97430; -. DR PaxDb; 10090-ENSMUSP00000104992; -. DR ProteomicsDB; 261195; -. DR Antibodypedia; 3705; 453 antibodies from 36 providers. DR DNASU; 20568; -. DR Ensembl; ENSMUST00000109367.10; ENSMUSP00000104992.4; ENSMUSG00000017002.15. DR GeneID; 20568; -. DR KEGG; mmu:20568; -. DR UCSC; uc008nuj.1; mouse. DR AGR; MGI:109297; -. DR CTD; 6590; -. DR MGI; MGI:109297; Slpi. DR VEuPathDB; HostDB:ENSMUSG00000017002; -. DR eggNOG; ENOG502SWIR; Eukaryota. DR GeneTree; ENSGT00730000111217; -. DR HOGENOM; CLU_105901_2_1_1; -. DR InParanoid; P97430; -. DR OMA; NLKCCKG; -. DR OrthoDB; 5472168at2759; -. DR PhylomeDB; P97430; -. DR TreeFam; TF338375; -. DR Reactome; R-MMU-6798695; Neutrophil degranulation. DR BioGRID-ORCS; 20568; 1 hit in 77 CRISPR screens. DR PRO; PR:P97430; -. DR Proteomes; UP000000589; Chromosome 2. DR RNAct; P97430; Protein. DR Bgee; ENSMUSG00000017002; Expressed in esophagus and 129 other cell types or tissues. DR ExpressionAtlas; P97430; baseline and differential. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI. DR GO; GO:0003677; F:DNA binding; ISO:MGI. DR GO; GO:0004866; F:endopeptidase inhibitor activity; IDA:UniProtKB. DR GO; GO:0019899; F:enzyme binding; ISO:MGI. DR GO; GO:0003729; F:mRNA binding; ISO:MGI. DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; ISS:UniProtKB. DR GO; GO:0019731; P:antibacterial humoral response; IMP:UniProtKB. DR GO; GO:0006955; P:immune response; IMP:UniProtKB. DR GO; GO:0045087; P:innate immune response; IMP:UniProtKB. DR GO; GO:0035821; P:modulation of process of another organism; ISO:MGI. DR GO; GO:0045071; P:negative regulation of viral genome replication; ISO:MGI. DR GO; GO:0032496; P:response to lipopolysaccharide; IMP:UniProtKB. DR CDD; cd00199; WAP; 1. DR Gene3D; 4.10.75.10; Elafin-like; 2. DR InterPro; IPR036645; Elafin-like_sf. DR InterPro; IPR008197; WAP_dom. DR PANTHER; PTHR19441:SF44; ANTILEUKOPROTEINASE; 1. DR PANTHER; PTHR19441; WHEY ACDIC PROTEIN WAP; 1. DR Pfam; PF00095; WAP; 2. DR PRINTS; PR00003; 4DISULPHCORE. DR SMART; SM00217; WAP; 2. DR SUPFAM; SSF57256; Elafin-like; 2. DR PROSITE; PS51390; WAP; 2. DR Genevisible; P97430; MM. PE 1: Evidence at protein level; KW Antibiotic; Antimicrobial; Direct protein sequencing; Disulfide bond; KW Immunity; Innate immunity; Protease inhibitor; Reference proteome; Repeat; KW Secreted; Serine protease inhibitor; Signal. FT SIGNAL 1..25 FT /evidence="ECO:0000269|PubMed:9126337" FT CHAIN 26..131 FT /note="Antileukoproteinase" FT /id="PRO_0000041356" FT DOMAIN 29..77 FT /note="WAP 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT DOMAIN 83..131 FT /note="WAP 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT REGION 85..131 FT /note="Elastase inhibitory domain" FT SITE 98..99 FT /note="Reactive bond for chymotrypsin, trypsin and FT elastase" FT /evidence="ECO:0000250|UniProtKB:P03973" FT DISULFID 36..65 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT DISULFID 44..69 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT DISULFID 52..64 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT DISULFID 58..73 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT DISULFID 90..119 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT DISULFID 97..123 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT DISULFID 106..118 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT DISULFID 112..127 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722" FT MUTAGEN 39..40 FT /note="KK->DD: Loss of antimicrobial activity." FT /evidence="ECO:0000269|PubMed:18322212" FT MUTAGEN 92 FT /note="K->D: Loss of antimicrobial activity; when FT associated with A-96." FT /evidence="ECO:0000269|PubMed:18322212" FT MUTAGEN 96 FT /note="R->D: Loss of antimicrobial activity; when FT associated with A-92." FT /evidence="ECO:0000269|PubMed:18322212" SQ SEQUENCE 131 AA; 14308 MW; A57C9E30FE711B8F CRC64; MKSCGLLPFT VLLALGILAP WTVEGGKNDA IKIGACPAKK PAQCLKLEKP QCRTDWECPG KQRCCQDACG SKCVNPVPIR KPVWRKPGRC VKTQARCMML NPPNVCQRDG QCDGKYKCCE GICGKVCLPP M //