SESN3_MOUSE
ID SESN3_MOUSE Reviewed; 492 AA.
AC Q9CYP7; Q3U2A0;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-APR-2001, sequence version 1.
DT 03-AUG-2022, entry version 126.
DE RecName: Full=Sestrin-3 {ECO:0000305};
DE EC=1.11.1.- {ECO:0000250|UniProtKB:P58004};
GN Name=Sesn3 {ECO:0000312|MGI:MGI:1922997};
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, and NOD; TISSUE=Embryo;
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 DISRUPTION PHENOTYPE.
RX PubMed=22958918; DOI=10.1016/j.cmet.2012.08.004;
RA Lee J.H., Budanov A.V., Talukdar S., Park E.J., Park H.L., Park H.W.,
RA Bandyopadhyay G., Li N., Aghajan M., Jang I., Wolfe A.M., Perkins G.A.,
RA Ellisman M.H., Bier E., Scadeng M., Foretz M., Viollet B., Olefsky J.,
RA Karin M.;
RT "Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.";
RL Cell Metab. 16:311-321(2012).
RN [3]
RP FUNCTION, INTERACTION WITH RRAGA; RRAGB; RRAGC AND RRAGD, TISSUE
RP SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=25259925; DOI=10.1016/j.cell.2014.08.038;
RA Peng M., Yin N., Li M.O.;
RT "Sestrins function as guanine nucleotide dissociation inhibitors for Rag
RT GTPases to control mTORC1 signaling.";
RL Cell 159:122-133(2014).
RN [4]
RP FUNCTION, INTERACTION WITH TORC2 COMPLEX, SUBCELLULAR LOCATION, AND
RP DISRUPTION PHENOTYPE.
RX PubMed=25377878; DOI=10.2337/db14-0539;
RA Tao R., Xiong X., Liangpunsakul S., Dong X.C.;
RT "Sestrin 3 protein enhances hepatic insulin sensitivity by direct
RT activation of the mTORC2-Akt signaling.";
RL Diabetes 64:1211-1223(2015).
CC -!- FUNCTION: May function as an intracellular leucine sensor that
CC negatively regulates the TORC1 signaling pathway (PubMed:25259925). May
CC also regulate the insulin-receptor signaling pathway through activation
CC of TORC2 (PubMed:25377878). This metabolic regulator may also play a
CC role in protection against oxidative and genotoxic stresses (By
CC similarity). May prevent the accumulation of reactive oxygen species
CC (ROS) through the alkylhydroperoxide reductase activity born by the N-
CC terminal domain of the protein (By similarity).
CC {ECO:0000250|UniProtKB:P58004, ECO:0000269|PubMed:25259925,
CC ECO:0000269|PubMed:25377878}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a hydroperoxide + L-cysteinyl-[protein] = an alcohol + S-
CC hydroxy-L-cysteinyl-[protein]; Xref=Rhea:RHEA:67124, Rhea:RHEA-
CC COMP:10131, Rhea:RHEA-COMP:17193, ChEBI:CHEBI:29950,
CC ChEBI:CHEBI:30879, ChEBI:CHEBI:35924, ChEBI:CHEBI:61973;
CC Evidence={ECO:0000250|UniProtKB:P58004};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67125;
CC Evidence={ECO:0000250|UniProtKB:P58004};
CC -!- SUBUNIT: Interacts with the GATOR2 complex which is composed of MIOS,
CC SEC13, SEH1L, WDR24 and WDR59; the interaction is not regulated by
CC leucine (By similarity). Interacts with RRAGA, RRAGB, RRAGC and RRAGD;
CC may function as a guanine nucleotide dissociation inhibitor for RRAGs
CC and regulate them (PubMed:25259925). Interacts with the TORC2 complex;
CC through RICTOR (PubMed:25377878). {ECO:0000250|UniProtKB:P58005,
CC ECO:0000269|PubMed:25259925, ECO:0000269|PubMed:25377878}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:25377878}.
CC -!- TISSUE SPECIFICITY: Detected in liver and skeletal muscles.
CC {ECO:0000269|PubMed:25259925}.
CC -!- DOMAIN: The N-terminal domain may have an alkylhydroperoxide reductase
CC activity. {ECO:0000250|UniProtKB:P58004}.
CC -!- DOMAIN: The C-terminal domain mediates interaction with GATOR2 through
CC which it regulates TORC1 signaling. {ECO:0000250|UniProtKB:P58004}.
CC -!- DISRUPTION PHENOTYPE: Liver-specific Sesn3 knockout mice display
CC insulin resistance and glucose intolerance (PubMed:25377878). Sesn2 and
CC Sesn3 double knockout mice display insulin resistance and glucose
CC intolerance (PubMed:22958918). Triple knockout mice lacking Sesn1,
CC Sesn2 and Sesn3 do not display an embryonic lethal phenotype since they
CC are born at an expected Mendelian ratio. Moreover, they are not
CC distinguishable from their wild-type littermate. However, their
CC survival at 10 days is dramatically affected. This is associated with a
CC constitutive activation of TORC1 signaling in the liver, heart and
CC skeletal muscle during postnatal fasting, that occurs between birth and
CC suckling (PubMed:25259925). {ECO:0000269|PubMed:22958918,
CC ECO:0000269|PubMed:25259925, ECO:0000269|PubMed:25377878}.
CC -!- SIMILARITY: Belongs to the sestrin family. {ECO:0000305}.
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; AK017464; BAB30755.1; -; mRNA.
DR EMBL; AK155398; BAE33242.1; -; mRNA.
DR CCDS; CCDS22820.1; -.
DR RefSeq; NP_084537.2; NM_030261.4.
DR AlphaFoldDB; Q9CYP7; -.
DR SMR; Q9CYP7; -.
DR IntAct; Q9CYP7; 1.
DR STRING; 10090.ENSMUSP00000034507; -.
DR iPTMnet; Q9CYP7; -.
DR PhosphoSitePlus; Q9CYP7; -.
DR MaxQB; Q9CYP7; -.
DR PaxDb; Q9CYP7; -.
DR PRIDE; Q9CYP7; -.
DR ProteomicsDB; 256781; -.
DR Antibodypedia; 31660; 224 antibodies from 30 providers.
DR DNASU; 75747; -.
DR Ensembl; ENSMUST00000208222; ENSMUSP00000146362; ENSMUSG00000032009.
DR GeneID; 75747; -.
DR KEGG; mmu:75747; -.
DR UCSC; uc009oej.1; mouse.
DR CTD; 143686; -.
DR MGI; MGI:1922997; Sesn3.
DR VEuPathDB; HostDB:ENSMUSG00000032009; -.
DR eggNOG; KOG3746; Eukaryota.
DR GeneTree; ENSGT00950000183168; -.
DR HOGENOM; CLU_020429_2_0_1; -.
DR InParanoid; Q9CYP7; -.
DR OMA; NSLNERM; -.
DR OrthoDB; 588598at2759; -.
DR PhylomeDB; Q9CYP7; -.
DR TreeFam; TF314230; -.
DR Reactome; R-MMU-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-MMU-9639288; Amino acids regulate mTORC1.
DR Reactome; R-MMU-9755511; KEAP1-NFE2L2 pathway.
DR BioGRID-ORCS; 75747; 1 hit in 72 CRISPR screens.
DR ChiTaRS; Sesn3; mouse.
DR PRO; PR:Q9CYP7; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q9CYP7; protein.
DR Bgee; ENSMUSG00000032009; Expressed in ventromedial nucleus of hypothalamus and 233 other tissues.
DR ExpressionAtlas; Q9CYP7; baseline and differential.
DR Genevisible; Q9CYP7; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0061700; C:GATOR2 complex; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IEA:InterPro.
DR GO; GO:0070728; F:leucine binding; IBA:GO_Central.
DR GO; GO:0016684; F:oxidoreductase activity, acting on peroxide as acceptor; IBA:GO_Central.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IMP:UniProtKB.
DR GO; GO:0042149; P:cellular response to glucose starvation; ISO:MGI.
DR GO; GO:0071233; P:cellular response to leucine; IBA:GO_Central.
DR GO; GO:1990253; P:cellular response to leucine starvation; IBA:GO_Central.
DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB.
DR GO; GO:1904262; P:negative regulation of TORC1 signaling; IMP:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IBA:GO_Central.
DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0051896; P:regulation of protein kinase B signaling; IDA:MGI.
DR GO; GO:1901031; P:regulation of response to reactive oxygen species; IEA:InterPro.
DR GO; GO:0032868; P:response to insulin; IMP:UniProtKB.
DR GO; GO:0038203; P:TORC2 signaling; IMP:UniProtKB.
DR Gene3D; 1.20.1290.10; -; 1.
DR InterPro; IPR029032; AhpD-like.
DR InterPro; IPR006730; Sestrin.
DR PANTHER; PTHR12474; PTHR12474; 1.
DR Pfam; PF04636; PA26; 1.
DR SUPFAM; SSF69118; SSF69118; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Oxidoreductase; Reference proteome.
FT CHAIN 1..492
FT /note="Sestrin-3"
FT /id="PRO_0000221184"
FT REGION 62..243
FT /note="N-terminal domain; may mediate the
FT alkylhydroperoxide reductase activity"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT REGION 310..492
FT /note="C-terminal domain; mediates TORC1 regulation"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT ACT_SITE 121
FT /note="Cysteine sulfenic acid (-SOH) intermediate"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 386..389
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 398
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 463
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
SQ SEQUENCE 492 AA; 57021 MW; 8E8AD9CB45656827 CRC64;
MNRGGSSASA SANYLLCTNC RKVLRKDKRI RVSQPLTRGP SAFIPEKEVV QANTADERTN
FLVEEYSTSG RLDNITQVMS LHTQYLESFL RSQFYMLRMD GPLPLPDRHY IAIMAAARHQ
CSYLINMHVD EFLKTGGIAE WLNGLEYVPQ RLRNLNEINK LLAHRPWLIT KEHIQKLVKT
GENNWSLPEL VHAVVLLAHY HALASFVFGS GINPERDPGI ANGFRLISVS SFCVCDLAND
NSIENTSLAG SNFGIVDSLG ELEALMERMK RLQEDREDDE TTREEMTTRF EKEKKESLFV
VPGETLHAFP HSDFEDDVIV TADVSRYIED PSFGYEDFAR RGEEHLPTFR AQDYTWENHG
FSLVNRLYSD IGHLLDEKFR MVYNLTYNTM ATHEDVDTTT LRRALFNYVH CMFGIRYDDY
DYGEVNQLLE RSLKVYIKTV TCYPERTTKR MYDSYWRQFT HSEKVHVNLL LMEARMQAEL
LYALRAITRH LT
