UniProt:P58004 SESN2

chain
  • chain:1-480
checksum 9C13371316D84060
comment
  • 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).CATALYTIC ACTIVITY a hydroperoxide + L-cysteinyl-[protein] = S-hydroxy-L-cysteinyl-[protein] + an alcoholSUBUNIT Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:35114100, PubMed:35831510, PubMed:36528027). Conveys leucine availability via direct interaction with SEH1L and WDR24 components of the GATOR2 complex (PubMed:35831510, PubMed:36528027). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). May interact with the TORC2 complex (By similarity). Interacts with KEAP1, RBX1, SQSTM and ULK1; to regulate the degradation of KEAP1 (PubMed:23274085, PubMed:25040165). May also associate with the complex composed of TSC1, TSC2 and the AMP-responsive protein kinase/AMPK to regulate TORC1 signaling (PubMed:18692468). May interact with PRDX1 (PubMed:15105503).INTERACTION Widely expressed.INDUCTION Up-regulated by hypoxia and DNA damage (PubMed:12203114). Up-regulated by treatments inducing endoplasmic reticulum stress (PubMed:24947615).DOMAIN The N-terminal domain has an alkylhydroperoxide reductase activity.DOMAIN The C-terminal domain mediates interaction with GATOR2 through which it regulates TORC1 signaling.PTM Phosphorylated by ULK1 at multiple sites.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).SIMILARITY Belongs to the sestrin family.
crossReference
databaseName UniProt
dbId 64340
description
  • recommendedName: fullName evidence="23"Sestrin-2 ecNumber evidence="24"1.11.1.- alternativeName: fullName evidence="21"Hypoxia-induced gene
displayName UniProt:P58004 SESN2
geneName
  • SESN2
  • Hi95
  • SEST2
identifier P58004
isSequenceChanged false
keyword
  • 3D-structure
  • Acetylation
  • Cytoplasm
  • Isopeptide bond
  • Oxidoreductase
  • Phosphoprotein
  • Proteomics identification
  • Reference proteome
  • Ubl conjugation
modified [InstanceEdit:9939033] Weiser, Joel, 2025-02-21
moleculeType Protein
name
  • SESN2
otherIdentifier
  • 11718324_s_at
  • 11718325_at
  • 16661544
  • 223195_PM_s_at
  • 223195_s_at
  • 223196_PM_s_at
  • 223196_s_at
  • 2327393
  • 2327394
  • 2327395
  • 2327396
  • 2327397
  • 2327402
  • 2327403
  • 2327404
  • 2327406
  • 2327407
  • 2327408
  • 2327409
  • 2327410
  • 2327411
  • 2327412
  • 2327414
  • 2327415
  • 48062_at
  • 55022_at
  • 7899436
  • 83667
  • A_23_P35082
  • GE63362
  • GO:0001932
  • GO:0004601
  • GO:0005092
  • GO:0005515
  • GO:0005634
  • GO:0005737
  • GO:0005739
  • GO:0005765
  • GO:0005829
  • GO:0006111
  • GO:0006629
  • GO:0006635
  • GO:0007005
  • GO:0009749
  • GO:0016239
  • GO:0016491
  • GO:0016684
  • GO:0030308
  • GO:0030330
  • GO:0031588
  • GO:0031669
  • GO:0031932
  • GO:0032042
  • GO:0032542
  • GO:0032868
  • GO:0034198
  • GO:0034599
  • GO:0042149
  • GO:0042593
  • GO:0042731
  • GO:0044877
  • GO:0046323
  • GO:0051897
  • GO:0055085
  • GO:0070328
  • GO:0070534
  • GO:0070728
  • GO:0071230
  • GO:0071233
  • GO:0072593
  • GO:0085020
  • GO:0098754
  • GO:0098869
  • GO:0140311
  • GO:0141161
  • GO:1900182
  • GO:1901031
  • GO:1902010
  • GO:1903432
  • GO:1904262
  • GO:1904263
  • GO:1904504
  • GO:1990253
  • GO:1990316
  • HMNXSV003003062
  • Hs.8026.0.S1_3p_a_at
  • ILMN_1751598
  • PH_hs_0000852
  • TC01000377.hg
  • g13276608_3p_a_at
physicalEntity
referenceDatabase [ReferenceDatabase:2] UniProt
referenceGene
referenceTranscript
schemaClass ReferenceGeneProduct
secondaryIdentifier
  • SESN2_HUMAN
  • Q5T7D0
  • Q96SI5
sequenceLength 480
species [Species:48887] Homo sapiens
stId uniprot:P58004
url http://purl.uniprot.org/uniprot/P58004
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