SESN2
entrez
83667
canonical
uniprot
P58004
canonical
ensembl
ENSG00000130766
resolver
ensembl
ENSG00000285069
resolver
ensp
ENSP00000253063
resolver
ensp
ENSP00000496365
resolver
ensp
ENSP00000643613
resolver
enst
ENST00000253063
resolver
enst
ENST00000645231
resolver
genesymbol
SESN2
resolver
genesymbol_syn
Hi95
resolver
genesymbol_syn
SEST2
resolver
hgnc
HGNC:20746
resolver
uniprot
Q5T7D0
resolver
uniprot
Q96SI5
resolver
uniprot_entry
SESN2_HUMAN
resolver
uniprot_sec
Q5T7D0
resolver
uniprot_sec
Q96SI5
resolver
amino_acid_sequence
MIVADSECRAELKDYLRFAPGGVGDSGPGEEQRESRARRGPRGPSAFIPVEEVLREGAESLEQHLGLEALMSSGRVDNLAVVMGLHPDYFTSFWRLHYLLLHTDGPLASSWRHYIAIMAAARHQCSYLVGSHMAEFLQTGGDPEWLLGLHRAPEKLRKLSEINKLLAHRPWLITKEHIQALLKTGEHTWSLAELIQALVLLTHCHSLSSFVFGCGILPEGDADGSPAPQAPTPPSEQSSPPSRDPLNNSGGFESARDVEALMERMQQLQESLLRDEGTSQEEMESRFELEKSESLLVTPSADILEPSPHPDMLCFVEDPTFGYEDFTRRGAQAPPTFRAQDYTWEDHGYSLIQRLYPEGGQLLDEKFQAAYSLTYNTIAMHSGVDTSVLRRAIWNYIHCVFGIRYDDYDYGEVNQLLERNLKVYIKTVACYPEKTTRRMYNLFWRHFRHSEKVHVNLLLLEARMQAALLYALRAITRYMT
uniprot
proteins
ec_number
1.11.1.-
uniprot
proteins
function
FUNCTION: Functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway through the GATOR complex (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26586190, PubMed:26612684, PubMed:31586034, PubMed:35114100, PubMed:35831510, PubMed:36528027). In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents mTORC1 signaling (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26586190, PubMed:26612684, PubMed:31586034, PubMed:35114100, PubMed:35831510, PubMed:36528027). Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:26449471, PubMed:26586190, PubMed:35114100, PubMed:35831510, PubMed:36528027). This stress-inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses. May negatively regulate protein translation in response to endoplasmic reticulum stress, via mTORC1 (PubMed:24947615). May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085). May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress (PubMed:18692468). Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (PubMed:26612684). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (PubMed:19113821). {ECO:0000269|PubMed:15105503, ECO:0000269|PubMed:18692468, ECO:0000269|PubMed:19113821, ECO:0000269|PubMed:23274085, ECO:0000269|PubMed:24947615, ECO:0000269|PubMed:25263562, ECO:0000269|PubMed:25457612, ECO:0000269|PubMed:26449471, ECO:0000269|PubMed:26586190, ECO:0000269|PubMed:26612684, ECO:0000269|PubMed:35114100, ECO:0000269|PubMed:35831510, ECO:0000269|PubMed:36528027}.
uniprot
proteins
mass_dalton
54494
uniprot
proteins
mutagenesis
MUTAGEN 13; /note="K->A: About two-fold prolonged half-life in cycloheximide/CHX time course."; /evidence="ECO:0000269|PubMed:26586190"; MUTAGEN 86; /note="H->A: Loss of leucine-binding."; /evidence="ECO:0000269|PubMed:26586190"; MUTAGEN 87; /note="P->S: No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 113; /note="H->E: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with C-128."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 125; /note="C->S: Decreased alkylhydroperoxide reductase activity and loss of the ability to decrease intracellular reactive oxygen species. No effect on interaction with the GATOR2 complex. No effect on inhibition of TOR signaling."; /evidence="ECO:0000269|PubMed:15105503, ECO:0000269|PubMed:18692468, ECO:0000269|PubMed:26612684"; MUTAGEN 127; /note="Y->F: Decreased alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 128; /note="L->C: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with E-113."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 132; /note="H->A: Decreased alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 175; /note="K->A: Abolished 'Lys-63'-linked ubiquitination by RNF167."; /evidence="ECO:0000269|PubMed:35114100"; MUTAGEN 190; /note="S->W: Loss of interaction with GATOR2. No effect on leucine-binding. Unable to mediate leucine-induced inhibition of the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26449471, ECO:0000269|PubMed:36528027"; MUTAGEN 204; /note="C->S: No effect on alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 214; /note="C->S: No effect on alkylhydroperoxide reductase activity."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 258; /note="V->R: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with L-259 and R-261."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 259; /note="E->L: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with R-258 and R-261."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 261; /note="L->A: Decreased leucine-binding. Promotes interaction with RNF167."; /evidence="ECO:0000269|PubMed:26449471, ECO:0000269|PubMed:35114100, ECO:0000269|PubMed:36528027"; MUTAGEN 261; /note="L->R: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with R-258 and L-259."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 262..264; /note="MER->LMM: No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 264; /note="R->P: No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 314; /note="C->S: No effect on ability to decrease intracellular reactive oxygen species."; /evidence="ECO:0000269|PubMed:15105503"; MUTAGEN 336..337; /note="TF->AA: No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 340..341; /note="QD->AA: No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 373; /note="L->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-376."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 374; /note="T->A: Loss of leucine-binding. Constitutively interacts with the GATOR2 complex."; /evidence="ECO:0000269|PubMed:26586190"; MUTAGEN 375; /note="Y->A: Loss of leucine-binding."; /evidence="ECO:0000269|PubMed:26586190"; MUTAGEN 376; /note="N->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-373."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 385; /note="D->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-387."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 386; /note="T->A: Loss of leucine-binding. Constitutively interacts with the GATOR2 complex."; /evidence="ECO:0000269|PubMed:26586190"; MUTAGEN 387; /note="S->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-385."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 390; /note="R->A: Loss of leucine-binding. Promotes interaction with RNF167. Constitutively interacts with the GATOR2 complex."; /evidence="ECO:0000269|PubMed:26586190, ECO:0000269|PubMed:35114100"; MUTAGEN 399; /note="C->S: No effect on alkylhydroperoxide reductase activity. Altered ability to decrease intracellular reactive oxygen species. No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:15105503, ECO:0000269|PubMed:26612684"; MUTAGEN 406..407; /note="DD->AA: Loss of interaction with the GATOR2 complex. No effect on leucine-binding."; /evidence="ECO:0000269|PubMed:26586190, ECO:0000269|PubMed:35114100"; MUTAGEN 406; /note="D->A: No effect on alkylhydroperoxide reductase activity. Loss of interaction with the GATOR2 complex. Unable to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 407; /note="D->A: No effect on alkylhydroperoxide reductase activity. Loss of interaction with the GATOR2 complex. Unable to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 409; /note="D->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-411 and A-415."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 411; /note="G->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-409 and A-415."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 415; /note="Q->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-409 and A-411."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 419; /note="R->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-422 and A-426."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 422; /note="K->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-419 and A-426."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 426; /note="K->A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-419 and A-422."; /evidence="ECO:0000269|PubMed:26612684"; MUTAGEN 430; /note="C->S: No effect on alkylhydroperoxide reductase activity. Altered ability to decrease intracellular reactive oxygen species. No effect on the ability to inhibit the TORC1 signaling pathway."; /evidence="ECO:0000269|PubMed:15105503, ECO:0000269|PubMed:26612684"; MUTAGEN 444; /note="W->E: Loss of leucine-binding."; /evidence="ECO:0000269|PubMed:26586190"; MUTAGEN 444; /note="W->L: Decreased affinity for leucine. Requires increased leucine concentration to dissociate from GATOR2 and activate TORC1 signaling."; /evidence="ECO:0000269|PubMed:26586190"; MUTAGEN 451; /note="E->A: Decreased leucine-binding."; /evidence="ECO:0000269|PubMed:26449471"; MUTAGEN 451; /note="E->Q: Loss of leucine-binding. Constitutively interacts with the GATOR2 complex."; /evidence="ECO:0000269|PubMed:26586190
uniprot
proteins
post_translational_modification
PTM: Phosphorylated by ULK1 at multiple sites. {ECO:0000269|PubMed:25040165}.; PTM: Ubiquitinated at Lys-175 by RNF167 via 'Lys-63'-linked polyubiquitination in response to leucine deprivation: ubiquitination promotes SESN2-interaction with the GATOR2 complex, leading to inhibit the TORC1 signaling pathway (PubMed:35114100). Deubiquitinated at Lys-175 by STAMBPL1, promoting the TORC1 signaling pathway (PubMed:35114100). Ubiquitinated by RNF186; ubiquitination mediates proteasomal degradation (PubMed:31586034). {ECO:0000269|PubMed:31586034, ECO:0000269|PubMed:35114100}.
uniprot
proteins
protein_family
Sestrin family
uniprot
proteins
pubmed
11230166
uniprot
proteins
pubmed
12203114
uniprot
proteins
pubmed
12607115
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15105503
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16710414
uniprot
proteins
pubmed
18692468
uniprot
proteins
pubmed
19113821
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23274085
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24947615
uniprot
proteins
pubmed
25040165
uniprot
proteins
pubmed
25259925
uniprot
proteins
pubmed
25263562
uniprot
proteins
pubmed
25457612
uniprot
proteins
pubmed
26449471
uniprot
proteins
pubmed
26586190
uniprot
proteins
pubmed
26612684
uniprot
proteins
pubmed
31586034
uniprot
proteins
pubmed
35114100
uniprot
proteins
pubmed
35831510
uniprot
proteins
pubmed
36528027
uniprot
proteins
sequence_length
480
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15105503}.
uniprot
proteins