UCHL3_MOUSE
ID UCHL3_MOUSE Reviewed; 230 AA.
AC Q9JKB1; Q9EQX7;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 26-SEP-2001, sequence version 2.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L3;
DE Short=UCH-L3;
DE EC=3.4.19.12 {ECO:0000250|UniProtKB:P15374};
DE AltName: Full=Ubiquitin thioesterase L3;
GN Name=Uchl3;
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], DEVELOPMENTAL STAGE, AND TISSUE SPECIFICITY.
RC STRAIN=Swiss Webster / NIH;
RX PubMed=10713173; DOI=10.1128/mcb.20.7.2498-2504.2000;
RA Kurihara L.J., Semenova E., Levorse J.M., Tilghman S.M.;
RT "Expression and functional analysis of Uch-L3 during mouse development.";
RL Mol. Cell. Biol. 20:2498-2504(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC STRAIN=C57BL/6J; TISSUE=Kidney, and Liver;
RX PubMed=11341770; DOI=10.1006/bbrc.2001.4841;
RA Osawa Y., Wang Y.-L., Osaka H., Aoki S., Wada K.;
RT "Cloning, expression, and mapping of a mouse gene, Uchl4, highly homologous
RT to human and mouse Uchl3.";
RL Biochem. Biophys. Res. Commun. 283:627-633(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 DEVELOPMENTAL STAGE.
RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532;
RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.;
RT "Cleavage of the C-terminus of NEDD8 by UCH-L3.";
RL Biochem. Biophys. Res. Commun. 251:688-692(1998).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15884048; DOI=10.1002/hipo.20082;
RA Wood M.A., Kaplan M.P., Brensinger C.M., Guo W., Abel T.;
RT "Ubiquitin C-terminal hydrolase L3 (Uchl3) is involved in working memory.";
RL Hippocampus 15:610-621(2005).
RN [6]
RP DISRUPTION PHENOTYPE, FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16816367; DOI=10.2353/ajpath.2006.060085;
RA Sano Y., Furuta A., Setsuie R., Kikuchi H., Wang Y.L., Sakurai M., Kwon J.,
RA Noda M., Wada K.;
RT "Photoreceptor cell apoptosis in the retinal degeneration of Uchl3-
RT deficient mice.";
RL Am. J. Pathol. 169:132-141(2006).
RN [7]
RP DISRUPTION PHENOTYPE, FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=17460351; DOI=10.1538/expanim.56.71;
RA Kwon J.;
RT "The new function of two ubiquitin C-terminal hydrolase isozymes as
RT reciprocal modulators of germ cell apoptosis.";
RL Exp. Anim. 56:71-77(2007).
RN [8]
RP FUNCTION IN ENAC RECYCLING, AND SUBCELLULAR LOCATION.
RX PubMed=17967898; DOI=10.1074/jbc.m707989200;
RA Butterworth M.B., Edinger R.S., Ovaa H., Burg D., Johnson J.P.,
RA Frizzell R.A.;
RT "The deubiquitinating enzyme UCH-L3 regulates the apical membrane recycling
RT of the epithelial sodium channel.";
RL J. Biol. Chem. 282:37885-37893(2007).
RN [9]
RP DISRUPTION PHENOTYPE, FUNCTION IN ADIPOGENESIS AND INSULIN SIGNALING, AND
RP MUTAGENESIS OF CYS-95.
RX PubMed=19837878; DOI=10.1210/en.2009-0332;
RA Suzuki M., Setsuie R., Wada K.;
RT "Ubiquitin carboxyl-terminal hydrolase l3 promotes insulin signaling and
RT adipogenesis.";
RL Endocrinology 150:5230-5239(2009).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC 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 [11]
RP DISRUPTION PHENOTYPE.
RX PubMed=20380862; DOI=10.1016/j.neuint.2010.03.021;
RA Setsuie R., Suzuki M., Tsuchiya Y., Wada K.;
RT "Skeletal muscles of Uchl3 knockout mice show polyubiquitinated protein
RT accumulation and stress responses.";
RL Neurochem. Int. 56:911-918(2010).
RN [12]
RP FUNCTION.
RX PubMed=21762696; DOI=10.1016/j.febslet.2011.06.037;
RA Dennissen F.J., Kholod N., Hermes D.J., Kemmerling N., Steinbusch H.W.,
RA Dantuma N.P., van Leeuwen F.W.;
RT "Mutant ubiquitin (UBB(+1)) associated with neurodegenerative disorders is
RT hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3).";
RL FEBS Lett. 585:2568-2574(2011).
CC -!- FUNCTION: Deubiquitinating enzyme (DUB) that controls levels of
CC cellular ubiquitin through processing of ubiquitin precursors and
CC ubiquitinated proteins. Thiol protease that recognizes and hydrolyzes a
CC peptide bond at the C-terminal glycine of either ubiquitin or NEDD8.
CC Has a 10-fold preference for Arg and Lys at position P3'', and exhibits
CC a preference towards 'Lys-48'-linked ubiquitin chains. Deubiquitinates
CC ENAC in apical compartments, thereby regulating apical membrane
CC recycling. Indirectly increases the phosphorylation of IGFIR, AKT and
CC FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis.
CC Required for stress-response retinal, skeletal muscle and germ cell
CC maintenance. May be involved in working memory. Can hydrolyze UBB(+1),
CC a mutated form of ubiquitin which is not effectively degraded by the
CC proteasome. {ECO:0000269|PubMed:15884048, ECO:0000269|PubMed:16816367,
CC ECO:0000269|PubMed:17460351, ECO:0000269|PubMed:17967898,
CC ECO:0000269|PubMed:19837878, ECO:0000269|PubMed:21762696}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12; Evidence={ECO:0000250|UniProtKB:P15374};
CC -!- ACTIVITY REGULATION: Inhibited by monoubiquitin and diubiquitin.
CC {ECO:0000250}.
CC -!- SUBUNIT: Preferentially binds diubiquitin; the interaction does not
CC hydrolyze diubiquitin but, in vitro, inhibits the hydrolyzing activity
CC on other substrates. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11341770,
CC ECO:0000269|PubMed:17967898}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with highest levels in
CC brain, liver, heart, thymus, kidney and testis. Highly expressed in the
CC cauda epididymidis, in meiotic pachytene spermatocytes and post-meiotic
CC spematids. In the retina, enriched in the photoreceptor inner segment.
CC {ECO:0000269|PubMed:10713173, ECO:0000269|PubMed:11341770,
CC ECO:0000269|PubMed:16816367, ECO:0000269|PubMed:17460351}.
CC -!- DEVELOPMENTAL STAGE: Expressed at 8.5 dpc in structures required for
CC skeletal patterning. Highly expressed at 11 dpc, and decreases markedly
CC from 15 dpc. {ECO:0000269|PubMed:10713173, ECO:0000269|PubMed:9790970}.
CC -!- DISRUPTION PHENOTYPE: Mice have no developmental defects, are fertile,
CC and show normal T-cell differentiation. They have normal anxiety,
CC locomotor behavior, motor function and synaptic transmission, but show
CC defects in spatial learning and working memory. Exhibit stress-related
CC effects with profound apoptosis-mediated germ cell loss and also,
CC prominent retinal degeneration with photoreceptor cell apoptosis and
CC mitochondrial oxidative stress. Mice show reduced capacity for
CC adipocyte differentiation and impaired insulin responses.
CC {ECO:0000269|PubMed:15884048, ECO:0000269|PubMed:16816367,
CC ECO:0000269|PubMed:17460351, ECO:0000269|PubMed:19837878,
CC ECO:0000269|PubMed:20380862}.
CC -!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}.
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DR EMBL; AF247358; AAF64193.1; -; mRNA.
DR EMBL; AB033370; BAB20094.1; -; mRNA.
DR EMBL; BC048481; AAH48481.1; -; mRNA.
DR CCDS; CCDS27313.1; -.
DR PIR; JC7688; JC7688.
DR RefSeq; NP_057932.2; NM_016723.2.
DR AlphaFoldDB; Q9JKB1; -.
DR BMRB; Q9JKB1; -.
DR SMR; Q9JKB1; -.
DR BioGRID; 206165; 6.
DR IntAct; Q9JKB1; 2.
DR MINT; Q9JKB1; -.
DR STRING; 10090.ENSMUSP00000002289; -.
DR BindingDB; Q9JKB1; -.
DR MEROPS; C12.003; -.
DR iPTMnet; Q9JKB1; -.
DR PhosphoSitePlus; Q9JKB1; -.
DR SwissPalm; Q9JKB1; -.
DR REPRODUCTION-2DPAGE; IPI00311369; -.
DR REPRODUCTION-2DPAGE; Q9JKB1; -.
DR EPD; Q9JKB1; -.
DR jPOST; Q9JKB1; -.
DR MaxQB; Q9JKB1; -.
DR PaxDb; Q9JKB1; -.
DR PeptideAtlas; Q9JKB1; -.
DR PRIDE; Q9JKB1; -.
DR ProteomicsDB; 298190; -.
DR DNASU; 50933; -.
DR Ensembl; ENSMUST00000002289; ENSMUSP00000002289; ENSMUSG00000022111.
DR GeneID; 50933; -.
DR KEGG; mmu:50933; -.
DR UCSC; uc007uvw.1; mouse.
DR CTD; 7347; -.
DR MGI; MGI:1355274; Uchl3.
DR VEuPathDB; HostDB:ENSMUSG00000022111; -.
DR eggNOG; KOG1415; Eukaryota.
DR GeneTree; ENSGT00940000154925; -.
DR HOGENOM; CLU_054406_1_1_1; -.
DR InParanoid; Q9JKB1; -.
DR OMA; YVCFVKG; -.
DR OrthoDB; 1013351at2759; -.
DR PhylomeDB; Q9JKB1; -.
DR TreeFam; TF316166; -.
DR BRENDA; 3.4.19.12; 3474.
DR Reactome; R-MMU-5689603; UCH proteinases.
DR Reactome; R-MMU-8866652; Synthesis of active ubiquitin: roles of E1 and E2 enzymes.
DR Reactome; R-MMU-8951664; Neddylation.
DR BioGRID-ORCS; 50933; 1 hit in 72 CRISPR screens.
DR ChiTaRS; Uchl3; mouse.
DR PRO; PR:Q9JKB1; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q9JKB1; protein.
DR Bgee; ENSMUSG00000022111; Expressed in heart left ventricle and 73 other tissues.
DR ExpressionAtlas; Q9JKB1; baseline and differential.
DR Genevisible; Q9JKB1; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; ISO:MGI.
DR GO; GO:0101005; F:deubiquitinase activity; IDA:MGI.
DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; ISO:MGI.
DR GO; GO:0007628; P:adult walking behavior; IGI:MGI.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IDA:UniProtKB.
DR GO; GO:0042755; P:eating behavior; IGI:MGI.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; IDA:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:MGI.
DR GO; GO:0060041; P:retina development in camera-type eye; IMP:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 3.40.532.10; -; 1.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001578; Peptidase_C12_UCH.
DR InterPro; IPR036959; Peptidase_C12_UCH_sf.
DR PANTHER; PTHR10589; PTHR10589; 1.
DR Pfam; PF01088; Peptidase_C12; 1.
DR PRINTS; PR00707; UBCTHYDRLASE.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS00140; UCH_1; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Hydrolase; Phosphoprotein; Protease; Reference proteome;
KW Thiol protease; Ubl conjugation pathway.
FT CHAIN 1..230
FT /note="Ubiquitin carboxyl-terminal hydrolase isozyme L3"
FT /id="PRO_0000211062"
FT REGION 8..13
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000250|UniProtKB:P15374"
FT REGION 152..159
FT /note="Interaction with ubiquitin. Crossover loop which
FT restricts access of large ubiquitin adducts to the active
FT site"
FT /evidence="ECO:0000250|UniProtKB:P15374"
FT REGION 219..224
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000250|UniProtKB:P15374"
FT ACT_SITE 95
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10091"
FT ACT_SITE 169
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10091"
FT SITE 184
FT /note="Important for enzyme activity"
FT /evidence="ECO:0000250|UniProtKB:P09936"
FT MOD_RES 130
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P15374"
FT MUTAGEN 95
FT /note="C->S: No increase in phosphorylation of AKT1, FOXO1
FT and INSR. No increased expression of SLC2A1, FABP4 nor
FT ADIPOQ. Impaired formation of large lipid droplets."
FT /evidence="ECO:0000269|PubMed:19837878"
FT CONFLICT 205..207
FT /note="AIE -> VIK (in Ref. 1; AAF64193)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 230 AA; 26152 MW; F147991F3ED69AC3 CRC64;
MEGQRWLPLE ANPEVTNQFL KQLGLHPNWQ FVDVYGMEPE LLSMVPRPVC AVLLLFPITE
KYEVFRTEEE EKIKSQGQDV TSSVYFMKQT ISNACGTIGL IHAIANNKDK MHFESGSTLK
KFLEESVSMS PEERAKFLEN YDAIRVTHET SAHEGQTEAP SIDEKVDLHF IALVHVDGHL
YELDGRKPFP INHGKTSDET LLEDAIEVCK KFMERDPDEL RFNAIALSAA
