SESN2

Summary

SESN2 (sestrin 2, HGNC:20746) is a protein-coding gene on chromosome 1p35.3, encoding Sestrin-2 (P58004). Functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway through the GATOR complex.

This gene encodes a member of the sestrin family of PA26-related proteins. The encoded protein may function in the regulation of cell growth and survival. This protein may be involved in cellular response to different stress conditions.

Source: NCBI Gene 83667 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 93 total
• MANE Select transcript: NM_031459

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20746
Approved symbol	SESN2
Name	sestrin 2
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Aliases	SES2, DKFZp761M0212, HI95, SEST2
Ensembl gene	ENSG00000130766
Ensembl biotype	protein_coding
OMIM	607767
Entrez	83667

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 15 protein_coding

ENST00000253063, ENST00000862801, ENST00000862802, ENST00000862803, ENST00000862804, ENST00000862805, ENST00000862806, ENST00000862807, ENST00000929850, ENST00000929851, ENST00000929852, ENST00000929853, ENST00000929854, ENST00000960546, ENST00000960547

RefSeq mRNA: 1 — MANE Select: NM_031459 NM_031459

CCDS: CCDS321

Canonical transcript exons

ENST00000253063 — 10 exons

Exon	Start	End
ENSE00000896276	28279097	28279241
ENSE00000896277	28274825	28275015
ENSE00000896278	28274040	28274158
ENSE00000896279	28273358	28273508
ENSE00000896280	28272581	28272793
ENSE00000896281	28272284	28272466
ENSE00000896282	28271674	28271871
ENSE00000896283	28269183	28269248
ENSE00000956207	28280716	28282491
ENSE00001037175	28259518	28259937

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 90.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.6163 / max 371.1609, expressed in 1803 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1788	22.6163	1803

Top tissues by expression

141 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	90.99	gold quality
right ovary	UBERON:0002118	87.87	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.62	gold quality
left ovary	UBERON:0002119	86.52	gold quality
ovary	UBERON:0000992	86.10	gold quality
stromal cell of endometrium	CL:0002255	85.81	gold quality
mucosa of transverse colon	UBERON:0004991	85.57	gold quality
right lobe of liver	UBERON:0001114	85.51	gold quality
duodenum	UBERON:0002114	84.19	gold quality
blood	UBERON:0000178	83.54	gold quality
islet of Langerhans	UBERON:0000006	83.53	gold quality
adult mammalian kidney	UBERON:0000082	83.46	gold quality
esophagus mucosa	UBERON:0002469	83.02	gold quality
granulocyte	CL:0000094	82.55	gold quality
liver	UBERON:0002107	81.97	gold quality
placenta	UBERON:0001987	80.94	gold quality
kidney	UBERON:0002113	80.38	gold quality
transverse colon	UBERON:0001157	80.06	gold quality
pancreas	UBERON:0001264	79.95	gold quality
mucosa of stomach	UBERON:0001199	79.71	gold quality
bone marrow	UBERON:0002371	79.66	gold quality
bone element	UBERON:0001474	79.65	gold quality
esophagus	UBERON:0001043	79.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.51	gold quality
upper lobe of left lung	UBERON:0008952	79.34	gold quality
omental fat pad	UBERON:0010414	79.27	gold quality
cortex of kidney	UBERON:0001225	78.92	gold quality
right adrenal gland cortex	UBERON:0035827	78.91	gold quality
metanephros cortex	UBERON:0010533	78.84	gold quality
left uterine tube	UBERON:0001303	78.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6075	yes	37.90
E-ANND-3	no	1.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, NFE2L2, TP53

miRNA regulators (miRDB)

86 targeting SESN2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 40)

• results show that sestrins, a family of proteins whose expression is modulated by p53, are required for regeneration of peroxiredoxins containing Cys-SO(2)H (PMID:15105503)
• results suggest that, unlike Srx, Sesn 2 is not a sulfinic Prx reductase (PMID:19113821)
• depletion of Sestrin2 or Dram failed to affect autophagy in p53-deficient cells (PMID:19377293)
• Signalling by the AMP-activated protein kinase was also involved as a downstream target of sestrin2. (PMID:21418191)
• PDGFRbeta accumulation is associated with increased oxidative stress and cellular damage in SESN2 silenced human glioblastoma U87 cells. (PMID:21536039)
• In breast cancer cells SESN2 is associated with AMPK. (PMID:22363791)
• Sestrin-2 redistributes to neuronal soma in human immunodeficiency virus (HIV)-associated neurocognitive disorders. (PMID:22450766)
• Sesn2 is required for the Nrf2-mediated cytoprotective activity against hydrogen peroxide (PMID:22749810)
• The JNK pathway mediated sestrin 2 expression and contributed to autophagy induction, highlighting the relationship of sestrin 2 and autophagy and the JNK signaling pathway. (PMID:22982090)
• Sesn2 as a new energetic stress sensor, which appears to be protective against energetic stress-induced apoptosis that integrates the pro-survival function of Akt and the negative regulation of mTOR. (PMID:23238567)
• results show that ATF4-regulated SESN2 expression presents a new link between ER stress and mTOR inhibition and autophagy. (PMID:23916134)
• results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD (PMID:24046361)
• Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species. (PMID:24825887)
• knockdown of SESN2 using small RNA interference promotes cellular toxicity of angiotensin II, as well as a reduction in cell viability, exacerbation of oxidative stress, and stimulation of apoptosis. (PMID:24838122)
• Sestrin2 has a hepatoprotective role against chronic ER stress (PMID:24947615)
• Data indicate that sestrin2 expression is upregulated by dopamine D2 receptor. (PMID:25024286)
• Sesn2 is oncogenic in skin squamous cell carcinoma and melanoma. (PMID:25378405)
• an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2, is reported. (PMID:25457612)
• The findings suggested that a decreased expression of sestrin 2 is associated with an unfavorable prognosis, which suggests that it is a novel and crucial predictor for colorectal cancer metastasis. (PMID:25572852)
• knockdown of Sestrin2 using small RNA interference promotes cell apoptosis and reactive oxygen species production induced by oxLDL. (PMID:25692450)
• Data indicate that inactivation of Sestrin 2 (Sesn2) or nuclear factor erythroid 2-related factor 2 (Nrf2) induced reactive oxygen species-mediated proteasomal inhibition and platelet-derived growth factor receptor beta (Pdgfrbeta) accumulation. (PMID:25716320)
• SESN2-AMPK signaling could exert a protective effect against glucose deprivation-induced cell death and that this effect is mediated by restoration of mitochondrial function. (PMID:25778901)
• GAA promotes FoxO3 nuclear translocation and binding to the SESN2 enhancer. (PMID:25802279)
• Sestrin2 inhibits mTORC1 through modulation of GATOR complexes (PMID:25819761)
• Sesn2 is a potential tumor suppressor in lung epithelial cells. The expression level of Sesn2 may serve as a prognostic marker for Chinese lung cancer patients in the clinic. (PMID:25962159)
• Sestrin2: A Promising Therapeutic Target for Liver Diseases (PMID:26133704)
• Sestrin2 silencing strongly inhibits cytokine-induced cell death. (PMID:26313705)
• These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway. (PMID:26449471)
• this study presents the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. (PMID:26586190)
• Sesn2 has two subdomains. The N-terminal domain reduces alkylhydroperoxide radicals through its helix-turn-helix oxidoreductase motif, and the C-terminal domain interacts with GATOR2 and subsequently inhibits mTORC1. (PMID:26612684)
• The up-regulation of SESN2 by mitochondrial dysfunction requires binding to ATF4. (PMID:26771712)
• These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis. (PMID:26913956)
• the results support a model in which leucine selectively promotes dephosphorylation of Sestrin2. (PMID:27010498)
• isorhapontigenin treatment induces autophagy and inhibits bladder cancer growth through MAPK8-JUN-dependent transcriptional induction of SESN2 (PMID:27171279)
• Sesn2 ablation increased UVA-induced Nrf2 induction and inhibits UVA-induced ROS production, indicating that Sesn2 acts as an upstream regulator of Nrf2 (PMID:27463837)
• There was significant overexpression of serum sesn2 protein and mRNA levels in the Alzheimer’s Disease group compared to Mild Cognitive Impairment and the control group. (PMID:27567861)
• simple analysis of the reported “apo”-Sestrin2 structure reveals the clear presence of prominent, unmodeled electron density in the leucine-binding pocket that exactly accommodates the leucine observed in the higher resolution structure. (PMID:27649739)
• The results suggest that SESN2 increases degradation of HIF-1A via AMPK-PHD regulation that contributes to inhibition of in vitro and in vivo tumorigenesis. (PMID:27840318)
• The data are the first to indicate that SESN2 might be a novel prognostic marker for hepatocellular carcinoma (PMID:28118855)
• Knockdown of sesn2 aggravates atherosclerotic processes by increasing pro-inflammatory reactions and ER stress in the endothelium via an AMPK-dependent mechanism, suggesting that sesn2 might be a novel therapeutic target for atherosclerosis. (PMID:28215577)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sesn2	ENSDARG00000070012
mus_musculus	Sesn2	ENSMUSG00000028893
rattus_norvegicus	Sesn2	ENSRNOG00000042785
drosophila_melanogaster	Sesn	FBGN0034897
caenorhabditis_elegans	sesn-1	WBGENE00022279

Paralogs (2): SESN1 (ENSG00000080546), SESN3 (ENSG00000149212)

Protein

Protein identifiers

Sestrin-2 — P58004 (reviewed: P58004)

Alternative names: Hypoxia-induced gene

All UniProt accessions (1): P58004

UniProt curated annotations — full annotation on UniProt →

Function. Functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents mTORC1 signaling. Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway. 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. 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. May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress. Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein. Was originally reported to contribute to oxidative stress resistance by reducing PRDX1. However, this could not be confirmed.

Subunit / interactions. Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine. Conveys leucine availability via direct interaction with SEH1L and WDR24 components of the GATOR2 complex. Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them. May interact with the TORC2 complex. Interacts with KEAP1, RBX1, SQSTM and ULK1; to regulate the degradation of KEAP1. May also associate with the complex composed of TSC1, TSC2 and the AMP-responsive protein kinase/AMPK to regulate TORC1 signaling. May interact with PRDX1.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylated by ULK1 at multiple sites. 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. Deubiquitinated at Lys-175 by STAMBPL1, promoting the TORC1 signaling pathway. Ubiquitinated by RNF186; ubiquitination mediates proteasomal degradation.

Domain organisation. The N-terminal domain has an alkylhydroperoxide reductase activity. The C-terminal domain mediates interaction with GATOR2 through which it regulates TORC1 signaling.

Induction. Up-regulated by hypoxia and DNA damage. Up-regulated by treatments inducing endoplasmic reticulum stress.

Similarity. Belongs to the sestrin family.

RefSeq proteins (1): NP_113647* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006730	Sestrin	Family
IPR029032	AhpD-like	Homologous_superfamily

Pfam: PF04636

Catalyzed reactions (Rhea), 1 shown:

• a hydroperoxide + L-cysteinyl-[protein] = S-hydroxy-L-cysteinyl-[protein] + an alcohol (RHEA:67124)

UniProt features (92 total): mutagenesis site 44, helix 24, strand 7, region of interest 5, turn 3, binding site 3, modified residue 2, chain 1, cross-link 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
5DJ4	X-RAY DIFFRACTION	2.7
5T0N	X-RAY DIFFRACTION	3
6N0M	X-RAY DIFFRACTION	3.3
9LWF	ELECTRON MICROSCOPY	3.41
5CUF	X-RAY DIFFRACTION	3.5
9LVJ	ELECTRON MICROSCOPY	3.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58004-F1	82.50	0.68

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 125 (cysteine sulfenic acid (-soh) intermediate)

Ligand- & substrate-binding residues (3): 374–377; 386; 451

Post-translational modifications (3): 1, 249, 175

Mutagenesis-validated functional residues (44):

Position	Phenotype
13	about two-fold prolonged half-life in cycloheximide/chx time course.
86	loss of leucine-binding.
87	no effect on the ability to inhibit the torc1 signaling pathway.
113	no effect on the ability to inhibit the torc1 signaling pathway; when associated with c-128.
125	decreased alkylhydroperoxide reductase activity and loss of the ability to decrease intracellular reactive oxygen specie
127	decreased alkylhydroperoxide reductase activity. no effect on the ability to inhibit the torc1 signaling pathway.
128	no effect on the ability to inhibit the torc1 signaling pathway; when associated with e-113.
132	decreased alkylhydroperoxide reductase activity. no effect on the ability to inhibit the torc1 signaling pathway.
175	abolished ’lys-63’-linked ubiquitination by rnf167.
190	loss of interaction with gator2. no effect on leucine-binding. unable to mediate leucine-induced inhibition of the torc1
204	no effect on alkylhydroperoxide reductase activity. no effect on the ability to inhibit the torc1 signaling pathway.
214	no effect on alkylhydroperoxide reductase activity.
258	no effect on the ability to inhibit the torc1 signaling pathway; when associated with l-259 and r-261.
259	no effect on the ability to inhibit the torc1 signaling pathway; when associated with r-258 and r-261.
261	decreased leucine-binding. promotes interaction with rnf167.
261	no effect on the ability to inhibit the torc1 signaling pathway; when associated with r-258 and l-259.
262–264	no effect on the ability to inhibit the torc1 signaling pathway.
264	no effect on the ability to inhibit the torc1 signaling pathway.
314	no effect on ability to decrease intracellular reactive oxygen species.
336–337	no effect on the ability to inhibit the torc1 signaling pathway.
340–341	no effect on the ability to inhibit the torc1 signaling pathway.
373	no effect on the ability to inhibit the torc1 signaling pathway; when associated with a-376.
374	loss of leucine-binding. constitutively interacts with the gator2 complex.
375	loss of leucine-binding.
376	no effect on the ability to inhibit the torc1 signaling pathway; when associated with a-373.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-9639288	Amino acids regulate mTORC1
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711097	Cellular response to starvation
R-HSA-9711123	Cellular response to chemical stress

MSigDB gene sets: 353 (showing top): AHRARNT_01, GOBP_LIPID_MODIFICATION, GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOCC_VACUOLAR_MEMBRANE, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN

GO Biological Process (35): regulation of protein phosphorylation (GO:0001932), regulation of gluconeogenesis (GO:0006111), fatty acid beta-oxidation (GO:0006635), mitochondrion organization (GO:0007005), response to glucose (GO:0009749), positive regulation of macroautophagy (GO:0016239), negative regulation of cell growth (GO:0030308), DNA damage response, signal transduction by p53 class mediator (GO:0030330), mitochondrial DNA metabolic process (GO:0032042), response to insulin (GO:0032868), cellular response to amino acid starvation (GO:0034198), cellular response to oxidative stress (GO:0034599), TORC2 signaling (GO:0038203), cellular response to glucose starvation (GO:0042149), glucose homeostasis (GO:0042593), obsolete D-glucose import (GO:0046323), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), triglyceride homeostasis (GO:0070328), cellular response to amino acid stimulus (GO:0071230), cellular response to L-leucine (GO:0071233), reactive oxygen species metabolic process (GO:0072593), protein localization to plasma membrane (GO:0072659), cellular oxidant detoxification (GO:0098869), regulation of cAMP/PKA signal transduction (GO:0141161), positive regulation of protein localization to nucleus (GO:1900182), regulation of response to reactive oxygen species (GO:1901031), negative regulation of translation in response to endoplasmic reticulum stress (GO:1902010), regulation of TORC1 signaling (GO:1903432), negative regulation of TORC1 signaling (GO:1904262), positive regulation of TORC1 signaling (GO:1904263), positive regulation of lipophagy (GO:1904504), cellular response to leucine starvation (GO:1990253), cellular response to nutrient levels (GO:0031669), protein K63-linked ubiquitination (GO:0070534), protein K6-linked ubiquitination (GO:0085020)

GO Molecular Function (10): peroxidase activity (GO:0004601), GDP-dissociation inhibitor activity (GO:0005092), oxidoreductase activity, acting on peroxide as acceptor (GO:0016684), sulfiredoxin activity (GO:0032542), PH domain binding (GO:0042731), protein-containing complex binding (GO:0044877), L-leucine binding (GO:0070728), protein sequestering activity (GO:0140311), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), lysosomal membrane (GO:0005765), cytosol (GO:0005829), nucleotide-activated protein kinase complex (GO:0031588), TORC2 complex (GO:0031932), GATOR2 complex (GO:0061700), Atg1/ULK1 kinase complex (GO:1990316)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Cellular responses to stress	2
Transcriptional Regulation by TP53	1
Cellular response to starvation	1
Cellular response to chemical stress	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Generic Transcription Pathway	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular response to starvation	2
antioxidant activity	2
binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
protein phosphorylation	1
regulation of protein modification process	1
regulation of phosphorylation	1
gluconeogenesis	1
regulation of glucose metabolic process	1
regulation of carbohydrate biosynthetic process	1
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
organelle organization	1
response to hexose	1
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
mitochondrion	1
DNA metabolic process	1
response to peptide hormone	1
response to amino acid starvation	1
response to oxidative stress	1
cellular response to chemical stress	1
TOR signaling	1
carbohydrate homeostasis	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
acylglycerol homeostasis	1
response to amino acid	1
cellular response to acid chemical	1

Protein interactions and networks

STRING

1301 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SESN2	RBX1	P62877	939
SESN2	PRDX1	P35703	805
SESN2	KEAP1	Q14145	797
SESN2	STK11	Q15831	794
SESN2	SQSTM1	Q13501	768
SESN2	WDR24	Q96S15	767
SESN2	SZT2	Q5T011	758
SESN2	ULK1	O75385	756
SESN2	SAMTOR	Q1RMZ1	754
SESN2	TSC2	P49815	753
SESN2	RICTOR	Q6R327	733
SESN2	RASA1	P20936	725
SESN2	CASTOR1	Q8WTX7	723
SESN2	TP53	P04637	721
SESN2	EFNA5	P52803	687

IntAct

70 interactions, top by confidence:

A	B	Type	Score
WDR5	KMT2D	psi-mi:“MI:0914”(association)	0.910
WDR24	SESN2	psi-mi:“MI:0915”(physical association)	0.890
WDR24	SESN2	psi-mi:“MI:0914”(association)	0.890
SESN2	WDR24	psi-mi:“MI:0914”(association)	0.890
SESN2	WDR24	psi-mi:“MI:0915”(physical association)	0.890
RBBP5	KMT2D	psi-mi:“MI:0914”(association)	0.840
MIOS	SEC13	psi-mi:“MI:0914”(association)	0.790
SESN2	SQSTM1	psi-mi:“MI:0915”(physical association)	0.730
WDR24	SEC13	psi-mi:“MI:0914”(association)	0.730
WDR59	SEC13	psi-mi:“MI:0914”(association)	0.730
SQSTM1	SESN2	psi-mi:“MI:0915”(physical association)	0.730
SESN2	MIOS	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710

BioGRID (82): SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-Western), SQSTM1 (Affinity Capture-Western), SQSTM1 (Co-localization), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), SESN2 (Affinity Capture-MS), WDR24 (Reconstituted Complex)

ESM2 similar proteins: A2RRP1, B1AY13, D4A770, F4HZK4, O15327, O75153, P50851, P58003, P58004, P58005, P58006, P58043, Q01433, Q02356, Q0IHW8, Q0IIE6, Q0KK59, Q32NR9, Q3V1U8, Q4R4D7, Q4R6P7, Q54WU6, Q58CN8, Q5NVD7, Q5RA60, Q5RCB4, Q5RD58, Q5SW19, Q5TYW4, Q6DIR8, Q6NRB7, Q6P1Y8, Q80TR8, Q86VS3, Q8C456, Q8N336, Q8N3R3, Q8NFP9, Q91YN0, Q9CYP7

Diamond homologs: P58003, P58004, P58005, P58006, P58043, Q4R6P7, Q54WU6, Q58CN8, Q5RCB4, Q9CYP7, Q9W1K5, Q9Y6P5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
leucine	“down-regulates activity”	SESN2	“chemical inhibition”
SESN2	“down-regulates activity”	GATOR2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Amino acids regulate mTORC1	7	50.1×	2e-08
Formation of WDR5-containing histone-modifying complexes	5	47.4×	9e-06
Formation of the beta-catenin:TCF transactivating complex	5	21.5×	2e-04
Activation of anterior HOX genes in hindbrain development during early embryogenesis	5	16.3×	5e-04
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	5	14.8×	7e-04
Neddylation	5	8.5×	7e-03
Cellular responses to stress	6	7.9×	3e-03
Cellular responses to stimuli	6	6.7×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to nutrient levels	5	80.7×	7e-07
negative regulation of TORC1 signaling	7	78.2×	9e-10
cellular response to amino acid starvation	5	54.8×	3e-06
positive regulation of TORC1 signaling	5	51.0×	4e-06
positive regulation of autophagy	5	35.9×	2e-05
ubiquitin-dependent protein catabolic process	5	12.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

93 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	72
Likely benign	7
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

1393 predictions. Top by Δscore:

Variant	Effect	Δscore
1:28259934:AGAGG:A	donor_loss	1.0000
1:28259935:GAG:G	donor_gain	1.0000
1:28259936:AGGT:A	donor_loss	1.0000
1:28259937:GGTA:G	donor_loss	1.0000
1:28259938:GTAAG:G	donor_loss	1.0000
1:28259939:T:G	donor_loss	1.0000
1:28269181:A:AG	acceptor_gain	1.0000
1:28269182:G:GG	acceptor_gain	1.0000
1:28269245:GGAG:G	donor_gain	1.0000
1:28269246:GAGG:G	donor_gain	1.0000
1:28269246:GAGGT:G	donor_loss	1.0000
1:28269248:GGTA:G	donor_loss	1.0000
1:28269249:G:C	donor_loss	1.0000
1:28269250:T:G	donor_loss	1.0000
1:28271867:TCATG:T	donor_gain	1.0000
1:28271870:TG:T	donor_gain	1.0000
1:28271871:GG:G	donor_gain	1.0000
1:28271872:G:GG	donor_gain	1.0000
1:28271873:T:G	donor_loss	1.0000
1:28272455:G:GT	donor_gain	1.0000
1:28272456:A:T	donor_gain	1.0000
1:28272464:CAGG:C	donor_loss	1.0000
1:28272466:GG:G	donor_loss	1.0000
1:28272467:G:A	donor_loss	1.0000
1:28272576:TCCA:T	acceptor_loss	1.0000
1:28272579:A:AG	acceptor_gain	1.0000
1:28272579:A:C	acceptor_loss	1.0000
1:28272579:AG:A	acceptor_gain	1.0000
1:28272580:G:GA	acceptor_gain	1.0000
1:28272580:GG:G	acceptor_gain	1.0000

AlphaMissense

3124 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:28274834:T:A	W344R	1.000
1:28274834:T:C	W344R	1.000
1:28274836:G:C	W344C	1.000
1:28274836:G:T	W344C	1.000
1:28272336:T:C	F136S	0.999
1:28272440:T:A	W171R	0.999
1:28272440:T:C	W171R	0.999
1:28272624:T:C	L194P	0.999
1:28274114:T:C	F326L	0.999
1:28274116:C:A	F326L	0.999
1:28274116:C:G	F326L	0.999
1:28274847:G:A	G348D	0.999
1:28274972:C:A	R390S	0.999
1:28275009:G:A	G402D	0.999
1:28275009:G:T	G402V	0.999
1:28279113:T:C	Y410H	0.999
1:28279151:G:C	K422N	0.999
1:28279151:G:T	K422N	0.999
1:28279163:G:C	K426N	0.999
1:28279163:G:T	K426N	0.999
1:28272304:T:G	C125W	0.998
1:28272335:T:C	F136L	0.998
1:28272337:T:A	F136L	0.998
1:28272337:T:G	F136L	0.998
1:28272426:T:C	L166P	0.998
1:28272435:G:C	R169P	0.998
1:28272608:T:A	W189R	0.998
1:28272608:T:C	W189R	0.998
1:28274835:G:C	W344S	0.998
1:28275008:G:C	G402R	0.998

dbSNP variants (sampled 300 via entrez): RS1000071627 (1:28275921 G>A), RS1000243197 (1:28257585 C>G), RS1000341235 (1:28268704 G>A), RS1000354711 (1:28265224 G>A,T), RS1000443904 (1:28262833 TAGG>T), RS1000454851 (1:28274283 G>A), RS1000506782 (1:28273953 T>A), RS1000594634 (1:28275078 G>C), RS1000670872 (1:28274713 G>A), RS1000768226 (1:28281503 A>G), RS1000820820 (1:28280703 C>G,T), RS1000954015 (1:28263638 C>T), RS1001069492 (1:28263347 G>C,T), RS1001106250 (1:28280493 A>G), RS1001137995 (1:28269716 T>A,G)

Disease associations

OMIM: gene MIM:607767 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007725_28	Serum uric acid levels	8.000000e-09
GCST008972_121	Urate levels	1.000000e-09
GCST90011899_123	Aspartate aminotransferase levels	2.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004761	uric acid measurement
EFO:0004531	urate measurement
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

164 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, decreases expression, increases expression, increases methylation	9
Tunicamycin	decreases reaction, increases expression, increases reaction	6
sodium arsenite	affects reaction, increases expression, increases phosphorylation, affects cotreatment, increases abundance	5
Cyclosporine	affects expression, increases expression	5
Aflatoxin B1	affects expression, increases expression, increases methylation	5
bisphenol A	affects expression, affects cotreatment, increases methylation, increases expression	4
Acetylcysteine	decreases reaction, increases expression	4
Resveratrol	affects reaction, increases expression, decreases expression, decreases reaction	3
Arsenic Trioxide	decreases reaction, increases expression, affects binding, affects cotreatment	3
Acetaminophen	increases expression	3
Cannabidiol	affects cotreatment, increases expression	3
Formaldehyde	increases expression	3
methylmercuric chloride	increases expression	2
didecyldimethylammonium	increases expression	2
hydroquinone	increases expression	2
perfluorooctane sulfonic acid	increases expression	2
pifithrin	affects cotreatment, increases expression	2
monomethylarsonous acid	increases expression	2
motexafin gadolinium	affects cotreatment, decreases expression, increases expression, decreases reaction	2
nutlin 3	affects cotreatment, increases expression, decreases expression, decreases reaction	2
(+)-JQ1 compound	affects cotreatment, affects expression, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Ethanol	decreases expression, decreases reaction, increases reaction, increases expression, affects cotreatment	2
Benzene	increases expression	2
Cisplatin	increases expression	2
Copper	affects binding, increases expression	2
Dactinomycin	affects cotreatment, increases expression, decreases reaction	2
Drugs, Chinese Herbal	increases expression	2
Estradiol	decreases expression, increases expression	2
Fluorouracil	increases expression, affects reaction	2

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1BG	Abcam HEK293 SESN2 KO	Transformed cell line	Female
CVCL_B2F3	Abcam HeLa SESN2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.