SESN2_MOUSE
ID SESN2_MOUSE Reviewed; 480 AA.
AC P58043;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-APR-2001, sequence version 1.
DT 03-AUG-2022, entry version 129.
DE RecName: Full=Sestrin-2 {ECO:0000305};
DE EC=1.11.1.- {ECO:0000250|UniProtKB:P58004};
GN Name=Sesn2 {ECO:0000312|MGI:MGI:2651874};
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=DH10B; TISSUE=Mammary tumor;
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 [2]
RP FUNCTION, AND INTERACTION WITH TSC1; TSC2 AND AMPK.
RX PubMed=18692468; DOI=10.1016/j.cell.2008.06.028;
RA Budanov A.V., Karin M.;
RT "p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR
RT signaling.";
RL Cell 134:451-460(2008).
RN [3]
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 [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23274085; DOI=10.1016/j.cmet.2012.12.002;
RA Bae S.H., Sung S.H., Oh S.Y., Lim J.M., Lee S.K., Park Y.N., Lee H.E.,
RA Kang D., Rhee S.G.;
RT "Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation
RT of Keap1 and prevent oxidative liver damage.";
RL Cell Metab. 17:73-84(2013).
RN [5]
RP FUNCTION, INTERACTION WITH RRAGA; RRAGB; RRAGC AND RRAGD, TISSUE
RP SPECIFICITY, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF ARG-419; LYS-422 AND
RP LYS-426.
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 [6]
RP INTERACTION WITH SQSTM1 AND ULK1.
RX PubMed=25040165; DOI=10.1111/febs.12905;
RA Ro S.H., Semple I.A., Park H., Park H., Park H.W., Kim M., Kim J.S.,
RA Lee J.H.;
RT "Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of
RT p62/sequestosome-1.";
RL FEBS J. 281:3816-3827(2014).
RN [7]
RP FUNCTION, INDUCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24947615; DOI=10.1038/ncomms5233;
RA Park H.W., Park H., Ro S.H., Jang I., Semple I.A., Kim D.N., Kim M.,
RA Nam M., Zhang D., Yin L., Lee J.H.;
RT "Hepatoprotective role of Sestrin2 against chronic ER stress.";
RL Nat. Commun. 5:4233-4233(2014).
RN [8]
RP INTERACTION WITH TORC2 COMPLEX.
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: Functions as an intracellular leucine sensor that negatively
CC regulates the TORC1 signaling pathway through the GATOR complex. In
CC absence of leucine, binds the GATOR subcomplex GATOR2 and prevents
CC TORC1 signaling. Binding of leucine to SESN2 disrupts its interaction
CC with GATOR2 thereby activating the TORC1 signaling pathway
CC (PubMed:18692468, PubMed:25259925). This stress-inducible metabolic
CC regulator also plays a role in protection against oxidative and
CC genotoxic stresses. May negatively regulate protein translation in
CC response to endoplasmic reticulum stress, via TORC1 (PubMed:24947615).
CC May positively regulate the transcription by NFE2L2 of genes involved
CC in the response to oxidative stress by facilitating the SQSTM1-mediated
CC autophagic degradation of KEAP1 (PubMed:23274085). May also mediate
CC TP53 inhibition of TORC1 signaling upon genotoxic stress
CC (PubMed:18692468). Moreover, may prevent the accumulation of reactive
CC oxygen species (ROS) through the alkylhydroperoxide reductase activity
CC born by the N-terminal domain of the protein (By similarity). Was
CC originally reported to contribute to oxidative stress resistance by
CC reducing PRDX1 (By similarity). However, this could not be confirmed
CC (By similarity). {ECO:0000250|UniProtKB:P58004,
CC ECO:0000269|PubMed:18692468, ECO:0000269|PubMed:23274085,
CC ECO:0000269|PubMed:24947615, ECO:0000269|PubMed:25259925}.
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 negatively regulated
CC by leucine (By similarity). Interacts with RRAGA, RRAGB, RRAGC and
CC RRAGD; may function as a guanine nucleotide dissociation inhibitor for
CC RRAGs and regulate them (PubMed:25259925). May interact with the TORC2
CC complex (PubMed:25377878). Interacts with KEAP1, RBX1, SQSTM and ULK1;
CC to regulate the degradation of KEAP1 (PubMed:25040165). May also
CC associate with the complex composed of TSC1, TSC2 and the AMP-
CC responsive protein kinase/AMPK to regulate TORC1 signaling
CC (PubMed:18692468). May interact with PRDX1 (By similarity).
CC {ECO:0000250|UniProtKB:P58004, ECO:0000269|PubMed:18692468,
CC ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25259925,
CC ECO:0000269|PubMed:25377878}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P58004}.
CC -!- TISSUE SPECIFICITY: Detected in heart, liver and skeletal muscles (at
CC protein level). {ECO:0000269|PubMed:25259925}.
CC -!- INDUCTION: Up-regulated by treatments inducing endoplasmic reticulum
CC stress. {ECO:0000269|PubMed:24947615}.
CC -!- DOMAIN: The N-terminal domain has 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 -!- PTM: Phosphorylated by ULK1 at multiple sites.
CC {ECO:0000250|UniProtKB:P58004}.
CC -!- PTM: Ubiquitinated at Lys-175 by RNF167 via 'Lys-63'-linked
CC polyubiquitination in response to leucine deprivation: ubiquitination
CC promotes SESN2-interaction with the GATOR2 complex, leading to inhibit
CC the TORC1 signaling pathway. Deubiquitinated at Lys-175 by STAMBPL1,
CC promoting the TORC1 signaling pathway. Ubiquitinated by RNF186;
CC ubiquitination mediates proteasomal degradation.
CC {ECO:0000250|UniProtKB:P58004}.
CC -!- DISRUPTION PHENOTYPE: Sesn2 knockout mice are fully viable and do not
CC display any overt developmental abnormalities. When kept on high fat
CC diet, they display higher insulin resistance and glucose intolerance
CC (PubMed:22958918). The oxidative stress induced by acute lipogenesis
CC upon refeeding results in increased liver damages in the Sesn2 knockout
CC mice. Any condition, like obesity, that triggers chronic or acute
CC endoplasmic reticulum stresses have the same consequences in these mice
CC and can lead to liver fibrosis (PubMed:23274085, PubMed:24947615).
CC Sesn2 and Sesn3 double knockout mice display insulin resistance and
CC glucose intolerance (PubMed:22958918). Triple knockout mice lacking
CC Sesn1, Sesn2 and Sesn3 do not display an embryonic lethal phenotype
CC since they are born at an expected Mendelian ratio. Moreover, they are
CC not distinguishable from their wild-type littermates. 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:23274085, ECO:0000269|PubMed:24947615,
CC ECO:0000269|PubMed:25259925}.
CC -!- SIMILARITY: Belongs to the sestrin family. {ECO:0000305}.
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DR EMBL; BC005672; AAH05672.1; -; mRNA.
DR CCDS; CCDS18726.1; -.
DR RefSeq; NP_659156.1; NM_144907.1.
DR AlphaFoldDB; P58043; -.
DR SMR; P58043; -.
DR BioGRID; 231026; 38.
DR IntAct; P58043; 41.
DR MINT; P58043; -.
DR STRING; 10090.ENSMUSP00000030724; -.
DR iPTMnet; P58043; -.
DR PhosphoSitePlus; P58043; -.
DR EPD; P58043; -.
DR MaxQB; P58043; -.
DR PaxDb; P58043; -.
DR PRIDE; P58043; -.
DR ProteomicsDB; 255393; -.
DR Antibodypedia; 2971; 271 antibodies from 34 providers.
DR DNASU; 230784; -.
DR Ensembl; ENSMUST00000030724; ENSMUSP00000030724; ENSMUSG00000028893.
DR GeneID; 230784; -.
DR KEGG; mmu:230784; -.
DR UCSC; uc008vbj.1; mouse.
DR CTD; 83667; -.
DR MGI; MGI:2651874; Sesn2.
DR VEuPathDB; HostDB:ENSMUSG00000028893; -.
DR eggNOG; KOG3746; Eukaryota.
DR GeneTree; ENSGT00950000183168; -.
DR HOGENOM; CLU_020429_0_0_1; -.
DR InParanoid; P58043; -.
DR OMA; GSHMTEF; -.
DR OrthoDB; 588598at2759; -.
DR PhylomeDB; P58043; -.
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; 230784; 1 hit in 71 CRISPR screens.
DR ChiTaRS; Sesn2; mouse.
DR PRO; PR:P58043; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; P58043; protein.
DR Bgee; ENSMUSG00000028893; Expressed in granulocyte and 147 other tissues.
DR Genevisible; P58043; MM.
DR GO; GO:1990316; C:Atg1/ULK1 kinase complex; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR GO; GO:0005634; C:nucleus; IEA:InterPro.
DR GO; GO:0005092; F:GDP-dissociation inhibitor activity; IDA:UniProtKB.
DR GO; GO:0070728; F:leucine binding; ISS:UniProtKB.
DR GO; GO:0016684; F:oxidoreductase activity, acting on peroxide as acceptor; ISS:UniProtKB.
DR GO; GO:0140311; F:protein sequestering activity; ISS:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISS:UniProtKB.
DR GO; GO:0032542; F:sulfiredoxin activity; IEA:Ensembl.
DR GO; GO:0098869; P:cellular oxidant detoxification; ISS:UniProtKB.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISO:MGI.
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; ISO:MGI.
DR GO; GO:1990253; P:cellular response to leucine starvation; ISS:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:UniProtKB.
DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; IMP:UniProtKB.
DR GO; GO:0006635; P:fatty acid beta-oxidation; IGI:MGI.
DR GO; GO:0042593; P:glucose homeostasis; IGI:MGI.
DR GO; GO:0046323; P:glucose import; IMP:MGI.
DR GO; GO:0032042; P:mitochondrial DNA metabolic process; IMP:MGI.
DR GO; GO:0007005; P:mitochondrion organization; IMP:MGI.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR GO; GO:1904262; P:negative regulation of TORC1 signaling; IMP:UniProtKB.
DR GO; GO:1902010; P:negative regulation of translation in response to endoplasmic reticulum stress; IMP:UniProtKB.
DR GO; GO:1904504; P:positive regulation of lipophagy; IMP:MGI.
DR GO; GO:0016239; P:positive regulation of macroautophagy; ISS:UniProtKB.
DR GO; GO:1900182; P:positive regulation of protein localization to nucleus; ISS:UniProtKB.
DR GO; GO:0036091; P:positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling; IMP:MGI.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; ISS:UniProtKB.
DR GO; GO:2000479; P:regulation of cAMP-dependent protein kinase activity; IMP:MGI.
DR GO; GO:0006111; P:regulation of gluconeogenesis; IMP:MGI.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IMP:MGI.
DR GO; GO:1901031; P:regulation of response to reactive oxygen species; IEA:InterPro.
DR GO; GO:0009749; P:response to glucose; IMP:MGI.
DR GO; GO:0032868; P:response to insulin; IMP:MGI.
DR GO; GO:0070328; P:triglyceride homeostasis; IMP:MGI.
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 Acetylation; Cytoplasm; Isopeptide bond; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Ubl conjugation.
FT CHAIN 1..480
FT /note="Sestrin-2"
FT /id="PRO_0000221182"
FT REGION 20..43
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 66..239
FT /note="N-terminal domain; mediates the alkylhydroperoxide
FT reductase activity"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT REGION 221..251
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 272..291
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 308..480
FT /note="C-terminal domain; mediates TORC1 regulation"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT COMPBIAS 25..39
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 125
FT /note="Cysteine sulfenic acid (-SOH) intermediate"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 374..377
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 386
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 451
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT MOD_RES 249
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT CROSSLNK 175
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT MUTAGEN 419
FT /note="R->A: Unable to inhibit TORC1 signaling; when
FT associated with A-422 and A-426."
FT /evidence="ECO:0000269|PubMed:25259925"
FT MUTAGEN 422
FT /note="K->A: Unable to inhibit TORC1 signaling; when
FT associated with A-419 and A-426."
FT /evidence="ECO:0000269|PubMed:25259925"
FT MUTAGEN 426
FT /note="K->A: Unable to inhibit TORC1 signaling; when
FT associated with A-419 and A-422."
FT /evidence="ECO:0000269|PubMed:25259925"
SQ SEQUENCE 480 AA; 54377 MW; 11B1FF352E75C90F CRC64;
MIVADSECHS EIKGYLPFTR GGVAGPETRE EHREGQARRG SRGPSAFIPV EEILREGAES
LEQHLGLEAL MSSGRVDNLA VVMGLHPDYL SSFWRLHYLL LHTDGPLASS WRHYIAIMAA
ARHQCSYLVG SHMTEFLQTG GDPEWLLGLH RAPEKLRKLS EVNKLLAHRP WLITKEHIQA
LLKTGEHSWS LAELIQALVL LTHCHSLASF VFGCGILPEG DAEGSPASQA PSPPSEQGTP
PSGDPLNNSG GFEAARDVEA LMERMRQLQE SLLRDEGASQ EEMENRFELE KSESLLVTPS
ADILEPSPHP DILCFVEDPA FGYEDFTRRG TQAPPTFRAQ DYTWEDHGYS LIQRLYPEGG
QLLDEKFQVA CSLTYNTIAM HSGVDTSMLR RAIWNYIHCV FGIRYDDYDY GEVNQLLERN
LKIYIKTVAC YPEKTTRRMY NLFWRHFRHS EKVHVNLLLL EARMQAALLY ALRAITRYMT
