{"gene":"SESN2","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2002,"finding":"SESN2 (Hi95) is a stress-responsive gene transcriptionally induced by prolonged hypoxia, DNA damage (in a p53-dependent manner), and oxidative stress (p53-independent). Overexpression is toxic to many cell types, causing apoptosis or sensitization to stress, but conditional overexpression in MCF7 cells protects against hypoxia/glucose deprivation and H2O2-induced cell death.","method":"cDNA microarray, conditional overexpression (tet-off system), cell viability assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple expression and overexpression experiments, but no molecular partner identification or pathway reconstitution","pmids":["12203114"],"is_preprint":false},{"year":2016,"finding":"SESN2 suppresses prolonged NLRP3 inflammasome activation by inducing mitophagy in macrophages. Mechanistically, SESN2 (1) facilitates perinuclear clustering of mitochondria by mediating SQSTM1 aggregation and its binding to K63-linked ubiquitins on the mitochondrial surface ('mitochondrial priming'), and (2) activates autophagic machinery by increasing ULK1 protein levels. SESN2 expression in macrophages is induced by NOS2-derived NO. Sesn2-deficient mice show defective mitophagy and hyperactivation of inflammasomes with increased mortality in two sepsis models.","method":"Genetic knockout mice (two sepsis models), siRNA knockdown, immunofluorescence, co-immunoprecipitation, Western blot, ubiquitin binding assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal mechanistic experiments in macrophages and in vivo knockout models with multiple orthogonal methods, replicated in two sepsis models","pmids":["27337507"],"is_preprint":false},{"year":2016,"finding":"SESN2 expression is transcriptionally induced by ISO treatment via a MAPK8/JNK1-JUN-dependent mechanism: ISO triggers MAPK8-dependent JUN activation and JUN binding to an AP-1 site in the SESN2 promoter, leading to SESN2 transcriptional induction that is required for autophagy induction in bladder cancer cells.","method":"Promoter-binding (ChIP/AP-1 reporter), siRNA knockdown, kinase inhibitors, Western blot","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing JUN binding to SESN2 promoter plus loss-of-function, single lab","pmids":["27171279"],"is_preprint":false},{"year":2016,"finding":"UVB induces SESN2 expression in melanocytes through the p53 and AKT3 pathways; SESN2 negatively regulates UVB-induced DNA damage repair. UVA induces SESN2 through mitochondria (not Nrf2); SESN2 ablation increased UVA-induced Nrf2 induction and inhibited UVA-induced ROS production, identifying SESN2 as an upstream regulator of Nrf2.","method":"siRNA knockdown, pathway inhibitors, ROS measurement, DNA damage assays, immunoblot","journal":"Photochemistry and photobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway readouts, single lab, two orthogonal UV stimuli","pmids":["27463837"],"is_preprint":false},{"year":2017,"finding":"LSD1/KDM1A epigenetically represses SESN2 transcription by binding to its promoter. Pharmacological inhibition or selective ablation of LSD1 de-represses SESN2 expression, which then inhibits mTORC1 activity and promotes autophagy in neuroblastoma cells. SESN2 overexpression alone suffices to promote autophagy, and SESN2 loss reduces LSD1 inhibition-induced autophagy.","method":"ChIP (LSD1 binding to SESN2 promoter), LSD1 inhibitors (TCP, SP2509), siRNA/shRNA knockdown, mTORC1 activity assays, autophagy assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus pharmacological and genetic loss-of-function with multiple mechanistic readouts, consistent epistatic placement","pmids":["28783174"],"is_preprint":false},{"year":2018,"finding":"SESN2 facilitates Parkin translocation to defective mitochondria during mitophagy by interacting with ULK1 and assisting ULK1-mediated phosphorylation of Beclin1 at serine-14, which is required for Beclin1-Parkin binding prior to mitochondrial translocation. The trigger for SESN2 activation is mitochondrial superoxide. SESN2-mediated cytosolic Parkin-Beclin1 interaction is PINK1-independent, but mitochondrial translocation of Parkin is PINK1-dependent.","method":"Co-immunoprecipitation, siRNA knockdown, phosphorylation site mapping (S14-Beclin1), mitochondrial superoxide scavenging, mitophagy assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistatic dissection of PINK1-dependence, phosphorylation site identification, multiple orthogonal methods","pmids":["29330382"],"is_preprint":false},{"year":2018,"finding":"RBX1 is an E3 ubiquitin ligase for SESN2 that mediates K48-linked ubiquitination of SESN2 upon prolonged mitochondrial damage (CCCP treatment), leading to SESN2 degradation and increased cell death. Downregulation of RBX1 stabilizes SESN2, reduces mitochondrial ROS, and reduces cell death.","method":"Co-immunoprecipitation, ubiquitination assays (K48-linkage), siRNA knockdown, cell viability assays","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with K48 specificity, single lab","pmids":["29294217"],"is_preprint":false},{"year":2018,"finding":"SESN2 negatively regulates mTORC1 activity in an amino acid-sensing context in cow mammary epithelial cells. Amino acid starvation increases SESN2 expression; SESN2 overexpression suppresses mTORC1 activation, cell proliferation, and casein synthesis; SESN2 inhibition reverses these effects.","method":"Overexpression and inhibition experiments, mTORC1 pathway readouts (Western blot), cell proliferation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain and loss of function with multiple readouts, single lab; ortholog study consistent with mammalian SESN2 mechanism","pmids":["29500367"],"is_preprint":false},{"year":2018,"finding":"BDNF promotes ATF4 elevation in neurons in a TrkB-dependent, eIF2α-independent manner. ATF4 then directly mediates BDNF-induced transcriptional induction of SESN2, establishing BDNF→TrkB→ATF4→SESN2 as a neuroprotective signaling axis.","method":"Transcriptome analysis, ATF4 knockdown, TrkB signaling inhibition, Western blot, neuronal cultures","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic + genetic epistasis (ATF4 KD abrogates SESN2 induction), single lab","pmids":["29599707"],"is_preprint":false},{"year":2019,"finding":"SESN2 interacts with Parkin and p62/SQSTM1, promotes accumulation of Parkin to mitochondria, and thereby alleviates doxorubicin-caused inhibition of Parkin-mediated mitophagy. SESN2 knockout (by sgRNA) inhibits Parkin-mediated mitophagy, increases cardiomyocyte apoptosis, and worsens mitochondrial dysfunction; ectopic SESN2 expression rescues these effects.","method":"Co-immunoprecipitation, CRISPR sgRNA knockout, mitophagy assays, electron microscopy, echocardiography, rat model","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of SESN2-Parkin-p62 complex, genetic KO and rescue in vivo and in vitro, multiple orthogonal methods","pmids":["31199952"],"is_preprint":false},{"year":2019,"finding":"ER stress-induced CHOP transcription factor directly binds the SESN2 promoter in colorectal cancer cells, increasing SESN2 expression, which then promotes autophagy. DHA + oxaliplatin enhance CHOP binding to the SESN2 promoter.","method":"Chromatin immunoprecipitation (CHOP binding to SESN2 promoter), Western blot, autophagy assays, in vitro and in vivo","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating CHOP binding to SESN2 promoter, single lab, supported by functional autophagy readouts","pmids":["31337142"],"is_preprint":false},{"year":2020,"finding":"SESN2 localizes to mitochondria, as demonstrated by subcellular fractionation and live-cell imaging experiments, and can directly regulate mitochondrial functions through mTORC1-independent mechanisms.","method":"Subcellular fractionation, mitochondrial localization experiments, live imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional implication, single lab","pmids":["32287270"],"is_preprint":false},{"year":2020,"finding":"JMJD3 histone demethylase negatively regulates SESN2 transcription by reducing H3K27me3 tri-methylation in the SESN2 promoter region. JMJD3 inhibition or knockdown restores SESN2 expression and protects against doxorubicin-induced cardiomyopathy; JMJD3 overexpression aggravates cardiomyopathy in a SESN2-dependent manner.","method":"ChIP (H3K27me3 at SESN2 promoter), JMJD3 knockdown/overexpression, SESN2 rescue overexpression, Western blot, cardiac functional assays","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating H3K27me3 reduction at SESN2 promoter by JMJD3, epistatic rescue experiments, multiple orthogonal methods","pmids":["33117796"],"is_preprint":false},{"year":2021,"finding":"SESN2 is transcriptionally induced by the ER stress-activated transcription factor C/EBPβ in denervated skeletal muscle. Once induced, SESN2 inhibits mTORC1 to attenuate ER stress, and also activates autophagic machinery to facilitate SQSTM1/p62 aggregation on the mitochondrial surface, promoting mitophagy and protecting against muscle atrophy.","method":"Knockdown and overexpression (AAV delivery), denervation mouse model, Western blot, electron microscopy, immunofluorescence, mTORC1 activity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown/overexpression in vivo, multiple pathway readouts, single lab","pmids":["34429398"],"is_preprint":false},{"year":2021,"finding":"SESN2 promotes the formation of a complex between AMPK and LKB1 (as demonstrated by immunoprecipitation), thereby facilitating AMPK-T172 phosphorylation. This mechanism underlies globular adiponectin-induced AMPK activation and insulin sensitization in skeletal muscle; these effects are absent in SESN2-/- mice.","method":"Co-immunoprecipitation, SESN2 knockout mice, AMPK phosphorylation assays, insulin signaling readouts","journal":"Sports medicine and health science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating SESN2-AMPK-LKB1 complex, confirmed in KO mice, single lab","pmids":["36994173"],"is_preprint":false},{"year":2021,"finding":"SESN2 inhibits mTORC1 activity through interaction with the GATOR2 protein complex, preventing GATOR2's inhibitory effect on GATOR1, which stimulates GTPase activity of RagA/B, preventing mTORC1 lysosomal translocation and activation. This pathway is established as SESN2's primary mTORC1-inhibitory mechanism.","method":"Pathway analysis, protein interaction (GATOR2/GATOR1/Rag GTPases), cited as established mechanism in review context within original research paper","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — described as established mechanism across multiple papers in the corpus including PMID:32287270; pathway placement is well-replicated across independent labs","pmids":["32287270"],"is_preprint":false},{"year":2021,"finding":"SESN2 increases Nrf2 protein expression by enhancing p62-dependent autophagy in endothelial progenitor cells treated with angiotensin II, providing a mechanism linking SESN2 to antioxidant defense via the Keap1/Nrf2 axis.","method":"Western blot, siRNA knockdown of Nrf2, p62 autophagy assays, immunofluorescence, EPCs from human umbilical cord blood","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mechanistic follow-up with siRNA and pathway readouts, single lab","pmids":["33231566"],"is_preprint":false},{"year":2021,"finding":"PERK pathway upregulation increases SESN2 expression in porcine oocytes. SESN2 acts upstream of NRF2: SESN2 siRNA knockdown blocks NRF2 nuclear activation, while NRF2 inhibition does not affect SESN2 protein levels. SESN2 deficiency blocks nuclear NRF2 activity and disrupts spindle assembly during oocyte maturation.","method":"siRNA knockdown, Western blot, immunofluorescence, NRF2 inhibitor, porcine oocyte IVM","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic relationship established by siRNA and pharmacological inhibition with pathway directionality confirmed, single lab","pmids":["34923100"],"is_preprint":false},{"year":2023,"finding":"UPRmt upregulates SESN2 through the Eif2ak4/eIF2α/Atf4 transcriptional axis. SESN2 then promotes translocation of cytosolic Parkin and SQSTM1 to defective mitochondria using two functional domains required for interacting with Parkin and SQSTM1, respectively. SQSTM1 translocation to mitochondria is Parkin-dependent. SESN2-mediated cytosolic Parkin-SQSTM1 interaction is PINK1-independent, while mitochondrial translocation requires PINK1.","method":"siRNA/gene silencing, domain mutagenesis, co-immunoprecipitation, Sesn2-/- mice (intervertebral disc degeneration model), mitophagy assays","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis identifying SESN2 interaction domains, PINK1 epistasis, Sesn2-/- in vivo model, replicates and extends PMID:29330382","pmids":["36632468"],"is_preprint":false},{"year":2023,"finding":"p53-regulated SESN2 suppresses STAT3 activity by downregulating the PTPRD phosphatase (responsible for STAT3 dephosphorylation), thereby regulating cell proliferation and death via an mTORC1-independent mechanism. SESN1&2 inactivation in A549 cells accelerates proliferation and confers drug resistance without affecting mTORC1, but stimulates STAT3.","method":"SESN1&2 double inactivation in A549 cells, STAT3 phosphorylation assays, PTPRD expression analysis, cell proliferation and death assays","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic inactivation with mechanistic epistasis (PTPRD→STAT3), single lab, novel mechanism","pmids":["39985075"],"is_preprint":false},{"year":2023,"finding":"Melatonin-induced SESN2 inhibits hepatic gluconeogenesis via a SESN2-SHP signaling cascade that competes with BTG2 and inhibits CREBH-mediated gluconeogenic gene transcription, suppressing the CRBN-BTG2-CREBH signaling axis.","method":"Sesn2 and Shp silencing mice, primary hepatocytes, gene expression analysis, rescue experiments","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic silencing in vivo and in vitro with mechanistic epistasis, single lab","pmids":["37488285"],"is_preprint":false},{"year":2023,"finding":"FTO demethylase reduces m6A methylation of SESN2 mRNA, decreasing its stability. FTO deficiency promotes binding of IGF2BP1 to SESN2 mRNA at exon 9 m6A modification sites, enhancing SESN2 mRNA stability and elevating SESN2 protein expression, which activates AMPK-mTOR-dependent autophagy in NSCLC cells.","method":"m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA stability assays, IGF2BP1 RIP, site-specific m6A mapping, SESN2 knockdown","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq with mechanistic follow-up on mRNA stability via IGF2BP1, single lab","pmids":["38495179"],"is_preprint":false},{"year":2024,"finding":"SETDB1 histone methyltransferase collaborates with heterochromatin protein HP1β to deposit H3K9me3 on the SESN2 promoter, thereby repressing SESN2 expression. SESN2 mediates SETDB1's regulation of mitochondrial damage and oxidative stress in renal ischemia-reperfusion injury.","method":"ChIP (H3K9me3 at SESN2 promoter), co-immunoprecipitation (SETDB1-HP1β), SETDB1 knockdown and pharmacological inhibition, in vivo and in vitro I/R models","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating H3K9me3 at SESN2 promoter, Co-IP of SETDB1-HP1β complex, rescue experiments in vivo, multiple orthogonal methods","pmids":["39443993"],"is_preprint":false},{"year":2024,"finding":"SESN2 promotes the interaction between SESN2 and RPN2 (ribophorin II) in response to leucine binding. RPN2 overexpression activates the GSK3β/β-catenin pathway (increasing nuclear β-catenin), whereas RPN2 knockdown combined with leucine rescues GSK3β phosphorylation effects, supporting SESN2-mediated promotion of C2C12 myoblast differentiation via the GSK3β/β-catenin pathway.","method":"Co-immunoprecipitation (SESN2-RPN2 interaction), RPN2 overexpression and knockdown, RNA sequencing, Western blot, β-catenin nuclear translocation assays, in vivo muscle injury model","journal":"Journal of the science of food and agriculture","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating SESN2-RPN2 interaction, epistatic rescue experiments, single lab","pmids":["38551359"],"is_preprint":false},{"year":2024,"finding":"SESN2 knockdown in brain tissue increases mTOR/HIF-1α pathway activity and enhances glycolysis (increased HK2, PFKM, PKM1, PKM2, GLUT1, and lactate levels), worsening cerebral ischemia-reperfusion injury. mTOR inhibition with rapamycin reverses these effects, demonstrating that SESN2 regulates glycolysis via mTOR/HIF-1α.","method":"Lentiviral SESN2 shRNA knockdown, MCAO mouse model, rapamycin rescue, Western blot, immunofluorescence, lactate assay","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic knockdown with rapamycin rescue establishes epistatic pathway, single lab","pmids":["40032632"],"is_preprint":false},{"year":2025,"finding":"KSHV-encoded vCyclin (a Cyclin D homolog) directly interacts with SESN2 and recruits the deubiquitinase OTUB1, blocking SESN2 polyubiquitination and proteasomal degradation, thereby stabilizing and upregulating SESN2. vCyclin lysine at residue 74 is crucial for cytosolic localization, OTUB1 recruitment, and SESN2 upregulation. Stabilized SESN2 activates AMPK to support survival of KSHV-driven primary effusion lymphoma cells.","method":"Co-immunoprecipitation (vCyclin-SESN2-OTUB1 complex), site-directed mutagenesis (K74 of vCyclin), ubiquitination assays, AMPK activity assays, cell survival assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of key residue, ubiquitination assays, functional downstream readout, single rigorous study with multiple orthogonal methods","pmids":["41196342"],"is_preprint":false},{"year":2025,"finding":"SESN2 directly binds AKT1 and promotes its phosphorylation at Ser473, which activates NRF2 nuclear localization to inhibit ferroptosis. Hepatocyte-specific AAV-mediated SESN2 knockdown abolishes the hepatoprotective effects of Yakuchinone A, establishing SESN2 as its primary pharmacological target in hepatic ischemia-reperfusion injury.","method":"AAV-mediated hepatocyte-specific overexpression/knockdown in vivo, co-immunoprecipitation (SESN2-AKT1), AKT1 phosphorylation assays, NRF2 nuclear translocation, rescue-of-function experiments","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vivo genetic rescue, single lab, novel physical interaction claim","pmids":["42105713"],"is_preprint":false},{"year":2025,"finding":"SESN2 interacts with SCAP (SREBP cleavage-activating protein) to deactivate SREBP1-mediated transcription of lipogenic enzymes in chondrocytes, and overexpression of Sesn2 in mice prevents obesity-related cartilage lipogenesis and OA progression.","method":"Co-immunoprecipitation (SESN2-SCAP), SREBP1 target gene assays, AAV-mediated Sesn2 overexpression in DMM mouse model, Western blot, histology","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of SESN2-SCAP, in vivo overexpression rescue, single lab","pmids":["40822351"],"is_preprint":false},{"year":2025,"finding":"SESN2 deficiency reduces PRDX6 K209 lactylation, a modification required for PRDX6-mediated redox homeostasis; quantitative co-immunoprecipitation showed PRDX6 interacts with GPX4, and this interaction is markedly weakened by K209R mutation. Re-expression of wild-type PRDX6 but not K209R mutant rescues SESN2 deficiency-induced oxidative stress and ferroptosis in granulosa cells.","method":"Quantitative co-immunoprecipitation, site-directed mutagenesis (K209R), lactylation analysis, SESN2 deficiency models (in vitro/in vivo), rescue experiments","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, and rescue experiments establishing SESN2-PRDX6-GPX4 axis, single lab","pmids":["41966311"],"is_preprint":false},{"year":2023,"finding":"SESN2 overexpression promotes MVB (multivesicular body) degradation by inhibiting Rab-7a ubiquitination, thereby promoting autophagosome-lysosome fusion. Additionally, SESN2 promotes TFEB nuclear translocation via the mTOR pathway to enhance lysosomal function, reducing exosome secretion from BSA-injured tubular cells.","method":"RNA-seq, IP-MS, Western blot, TFEB nuclear translocation assay, Rab-7a ubiquitination assay, SESN2 overexpression in HK2 cells","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS and ubiquitination assay, TFEB nuclear translocation readout, single lab","pmids":["40612680"],"is_preprint":false},{"year":2018,"finding":"miR-182-5p directly represses SESN2 expression by targeting its 3'-UTR (validated by luciferase reporter and RNP-IP), and ATO-mediated suppression of miR-182-5p leads to stabilization of SESN2 mRNA through AGO2-dependent gene silencing relief.","method":"Luciferase reporter assay (SESN2 3'UTR), ribonucleoprotein immunoprecipitation (RNP-IP/AGO2), miR-182-5p mimic transfection, mRNA stability assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus RNP-IP demonstrating AGO2-dependent silencing of SESN2 mRNA, single lab","pmids":["29662624"],"is_preprint":false}],"current_model":"SESN2 is a p53-regulated, stress-inducible protein that inhibits mTORC1 by binding GATOR2 (disrupting GATOR1 inhibition and thereby suppressing RagA/B-dependent mTORC1 lysosomal recruitment), promotes mitophagy by facilitating ULK1-mediated Beclin1-S14 phosphorylation and Parkin/SQSTM1 translocation to damaged mitochondria (via two distinct SESN2 functional domains), is post-translationally regulated by K48-linked ubiquitination through RBX1 and stabilized by KSHV vCyclin/OTUB1-mediated deubiquitination, is transcriptionally controlled by p53, C/EBPβ, ATF4/CHOP, and epigenetically repressed by LSD1 (H3K4me2) and JMJD3/SETDB1 (H3K27me3/H3K9me3), acts upstream of Nrf2 to regulate ROS, suppresses STAT3 by maintaining PTPRD phosphatase levels, interacts with SCAP to inhibit SREBP1-mediated lipogenesis, binds AKT1 to promote its Ser473 phosphorylation, and localizes to mitochondria to regulate mitochondrial function independently of mTORC1."},"narrative":{"mechanistic_narrative":"SESN2 is a stress-inducible cytoprotective protein that integrates signals from hypoxia, DNA damage, oxidative stress, ER stress, and nutrient deprivation to restrain mTORC1 signaling and promote autophagy/mitophagy [PMID:12203114, PMID:28783174, PMID:34429398]. Its principal anabolic-restraining function is inhibition of mTORC1: SESN2 binds the GATOR2 complex, relieving GATOR2 suppression of GATOR1, which stimulates RagA/B GTPase activity and prevents lysosomal recruitment/activation of mTORC1 in amino-acid- and stress-sensing contexts [PMID:32287270, PMID:29500367]. Independently of mTORC1, SESN2 drives selective clearance of damaged mitochondria: triggered by mitochondrial superoxide, it interacts with ULK1 to elevate ULK1 levels and promote ULK1-mediated phosphorylation of Beclin1 at Ser14, enabling cytosolic Parkin–Beclin1/SQSTM1 assembly and PINK1-dependent translocation of Parkin and SQSTM1 to damaged mitochondria via two distinct functional domains [PMID:29330382, PMID:36632468, PMID:27337507, PMID:31199952]. Through these activities SESN2 suppresses prolonged NLRP3 inflammasome activation and protects against tissue injury in sepsis, cardiomyopathy, and disc degeneration [PMID:27337507, PMID:31199952, PMID:36632468]. SESN2 also acts upstream of the NRF2 antioxidant program—enhancing NRF2 via p62-dependent autophagy and AKT1-Ser473 phosphorylation—and limits ferroptosis and ROS [PMID:27463837, PMID:33231566, PMID:34923100, PMID:42105713]. Beyond redox and autophagy control, SESN2 restrains lipogenesis by binding SCAP to block SREBP1 activation [PMID:40822351], suppresses STAT3 by maintaining the phosphatase PTPRD [PMID:39985075], and regulates AMPK activation by promoting AMPK–LKB1 complex formation [PMID:36994173]. SESN2 expression is tightly controlled: it is transcriptionally induced by p53, ATF4/CHOP, C/EBPβ, and JUN [PMID:12203114, PMID:29599707, PMID:31337142, PMID:34429398, PMID:27171279]; epigenetically repressed by LSD1, JMJD3, and SETDB1/HP1β at its promoter [PMID:28783174, PMID:33117796, PMID:39443993]; post-transcriptionally regulated by miR-182-5p and FTO/IGF2BP1-dependent m6A control [PMID:29662624, PMID:38495179]; and stabilized or degraded through K48-linked ubiquitination by RBX1 versus deubiquitination by OTUB1, the latter exploited by KSHV vCyclin to sustain AMPK-driven lymphoma survival [PMID:29294217, PMID:41196342].","teleology":[{"year":2002,"claim":"Established SESN2 as a stress-responsive gene, defining the inducing signals (hypoxia, p53-dependent DNA damage, p53-independent oxidative stress) and its context-dependent role in cell death versus protection.","evidence":"cDNA microarray and conditional (tet-off) overexpression with viability assays","pmids":["12203114"],"confidence":"Medium","gaps":["No molecular partner or pathway mechanism identified","Pro-death versus pro-survival switch unexplained"]},{"year":2016,"claim":"Defined SESN2 as a driver of mitophagy that limits inflammation, linking it mechanistically to SQSTM1-mediated mitochondrial priming and ULK1 upregulation in vivo.","evidence":"Sesn2-knockout mice in two sepsis models, Co-IP, ubiquitin-binding assays, and imaging in macrophages","pmids":["27337507"],"confidence":"High","gaps":["Domain mediating SQSTM1/ubiquitin engagement not mapped","Mechanism of ULK1 protein-level increase unresolved"]},{"year":2016,"claim":"Identified the JNK/JUN-AP1 axis and the p53/AKT3 and mitochondrial routes as distinct upstream inducers of SESN2, expanding the transcriptional input map and placing SESN2 upstream of Nrf2.","evidence":"ChIP/AP-1 reporter, kinase inhibitors, siRNA, ROS and DNA-damage assays across stimuli","pmids":["27171279","27463837"],"confidence":"Medium","gaps":["How SESN2 negatively regulates DNA-damage repair is unclear","Molecular link from SESN2 to Nrf2 not yet defined"]},{"year":2017,"claim":"Placed SESN2 within an epigenetic repression circuit, showing LSD1 (H3K4me2) at the promoter restrains SESN2-driven mTORC1 inhibition and autophagy.","evidence":"ChIP, LSD1 inhibitors/knockdown, mTORC1 and autophagy readouts in neuroblastoma","pmids":["28783174"],"confidence":"High","gaps":["Cofactors recruiting LSD1 to the SESN2 promoter unidentified"]},{"year":2018,"claim":"Resolved the molecular mechanism of SESN2-driven mitophagy: ULK1 interaction and Beclin1-S14 phosphorylation gate cytosolic Parkin assembly (PINK1-independent) prior to PINK1-dependent mitochondrial translocation.","evidence":"Reciprocal Co-IP, phosphosite mapping, superoxide scavenging, PINK1 epistasis","pmids":["29330382"],"confidence":"High","gaps":["Direct kinase/substrate biochemistry of the SESN2-ULK1-Beclin1 step not reconstituted"]},{"year":2018,"claim":"Defined post-translational and additional transcriptional control of SESN2, identifying RBX1 as a K48-linked E3 ligase driving SESN2 degradation, ATF4 as a BDNF/TrkB-driven inducer, and amino-acid-sensitive mTORC1 suppression.","evidence":"Co-IP/ubiquitination assays, transcriptome and ATF4 knockdown, gain/loss-of-function mTORC1 readouts","pmids":["29294217","29599707","29500367"],"confidence":"Medium","gaps":["RBX1 partner cullin/adaptor not defined","Degron on SESN2 not mapped"]},{"year":2019,"claim":"Confirmed the SESN2-Parkin-SQSTM1 mitophagy module in cardiac tissue and extended it to CHOP-driven transcriptional induction under ER stress, linking SESN2 to autophagic cytoprotection.","evidence":"Co-IP, CRISPR KO and rescue in rat cardiac model; ChIP of CHOP at SESN2 promoter","pmids":["31199952","31337142"],"confidence":"High","gaps":["Whether SESN2-Parkin binding is direct unresolved","Quantitative contribution of CHOP versus other TFs not parsed"]},{"year":2020,"claim":"Demonstrated mitochondrial localization of SESN2 and mTORC1-independent regulation of mitochondrial function, and consolidated the GATOR2-GATOR1-Rag mechanism as the primary mTORC1-inhibitory route.","evidence":"Subcellular fractionation and live imaging; pathway analysis of GATOR2/GATOR1/Rag interactions","pmids":["32287270"],"confidence":"Medium","gaps":["Mitochondrial submembrane location and import mechanism unknown","Direct structural basis of SESN2-GATOR2 binding not shown in these data"]},{"year":2021,"claim":"Broadened SESN2 regulatory inputs and outputs: C/EBPβ induction in atrophying muscle, AMPK-LKB1 complex promotion, p62-dependent NRF2 elevation, PERK-driven NRF2 epistasis, and JMJD3-mediated H3K27me3 repression.","evidence":"In vivo knockdown/overexpression, Co-IP, ChIP, siRNA/inhibitor epistasis across muscle, endothelial, and oocyte systems","pmids":["34429398","36994173","33231566","34923100","33117796"],"confidence":"High","gaps":["Whether SESN2-AMPK-LKB1 contact is direct unresolved","Stoichiometry and selectivity of SESN2 toward distinct effectors unclear"]},{"year":2023,"claim":"Identified domain-level and effector-level specificity: two SESN2 domains separately engage Parkin and SQSTM1 for UPRmt-induced mitophagy, while mTORC1-independent branches act through PTPRD-STAT3, SHP-CREBH gluconeogenesis control, m6A/IGF2BP1 mRNA stabilization, and Rab7a/TFEB-dependent lysosomal trafficking.","evidence":"Domain mutagenesis, PINK1 epistasis, Sesn2-/- models, genetic inactivation, MeRIP-seq, IP-MS, ubiquitination and TFEB translocation assays","pmids":["36632468","39985075","37488285","38495179","40612680"],"confidence":"High","gaps":["Boundaries and structures of the two functional domains not defined","How SESN2 lowers PTPRD mechanistically unknown"]},{"year":2024,"claim":"Extended SESN2 control of metabolism and redox: SETDB1/HP1β-mediated H3K9me3 repression, mTOR/HIF-1α-dependent glycolytic restraint, and leucine-induced SESN2-RPN2 signaling to GSK3β/β-catenin in myogenesis.","evidence":"ChIP, Co-IP, knockdown/inhibitor and rapamycin rescue in renal I/R, MCAO, and myoblast models","pmids":["39443993","40032632","38551359"],"confidence":"High","gaps":["Direct SESN2-RPN2 functional consequence on leucine sensing unclear","Connection between mitochondrial SESN2 and glycolytic output incompletely defined"]},{"year":2025,"claim":"Resolved deubiquitinase-mediated stabilization and new direct interactors: KSHV vCyclin/OTUB1 stabilizes SESN2 to drive AMPK and lymphoma survival, SESN2 binds AKT1 to drive Ser473 phosphorylation and NRF2-dependent anti-ferroptosis, binds SCAP to block SREBP1 lipogenesis, and supports PRDX6-K209 lactylation/GPX4 redox defense.","evidence":"Reciprocal Co-IP, residue mutagenesis (vCyclin K74, PRDX6 K209R), ubiquitination and AKT1 phosphorylation assays, AAV in vivo rescue","pmids":["41196342","42105713","40822351","41966311"],"confidence":"High","gaps":["Whether SESN2-AKT1 binding directly catalyzes Ser473 phosphorylation versus scaffolding unresolved","Structural basis of SESN2-SCAP interaction unknown"]},{"year":null,"claim":"How a single SESN2 protein selects among its many described effectors (GATOR2, ULK1/Parkin, AKT1, SCAP, AMPK-LKB1, RPN2) in a given cell state, and the structural basis for these competing interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model distinguishing the effector-binding surfaces","Determinants of mitochondrial versus cytosolic SESN2 partitioning unknown","Quantitative hierarchy among parallel SESN2 outputs not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,18,14]},{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[3,16,28]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11,5,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,18]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,5,18,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,3,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[20,24,27]}],"complexes":[],"partners":["GATOR2","ULK1","PARKIN","SQSTM1","SCAP","AKT1","RPN2","SETDB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P58004","full_name":"Sestrin-2","aliases":["Hypoxia-induced gene"],"length_aa":480,"mass_kda":54.5,"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)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P58004/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SESN2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SESN2","total_profiled":1310},"omim":[{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"607767","title":"SESTRIN 2; SESN2","url":"https://www.omim.org/entry/607767"},{"mim_id":"606103","title":"SESTRIN 1; SESN1","url":"https://www.omim.org/entry/606103"},{"mim_id":"188400","title":"DIGEORGE SYNDROME; DGS","url":"https://www.omim.org/entry/188400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SESN2"},"hgnc":{"alias_symbol":["SES2","DKFZp761M0212","HI95","SEST2"],"prev_symbol":[]},"alphafold":{"accession":"P58004","domains":[{"cath_id":"1.20.1290.10","chopping":"43-213","consensus_level":"medium","plddt":89.9081,"start":43,"end":213},{"cath_id":"-","chopping":"254-302_318-462","consensus_level":"medium","plddt":91.6622,"start":254,"end":462}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P58004","model_url":"https://alphafold.ebi.ac.uk/files/AF-P58004-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P58004-F1-predicted_aligned_error_v6.png","plddt_mean":81.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SESN2","jax_strain_url":"https://www.jax.org/strain/search?query=SESN2"},"sequence":{"accession":"P58004","fasta_url":"https://rest.uniprot.org/uniprotkb/P58004.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P58004/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P58004"}},"corpus_meta":[{"pmid":"12203114","id":"PMC_12203114","title":"Identification 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autophagy.","date":"2025","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/40834759","citation_count":2,"is_preprint":false},{"pmid":"40822351","id":"PMC_40822351","title":"SESN2 maintains cartilage homeostasis by SREBP1-mediated lipid metabolism during osteoarthritis progression.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40822351","citation_count":1,"is_preprint":false},{"pmid":"40842769","id":"PMC_40842769","title":"Neuroprotective Effects of Phosphodiesterase Inhibitors on Sestrin-2 (SESN2) Expression and Autophagy in Alzheimer's Disease Model.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/40842769","citation_count":1,"is_preprint":false},{"pmid":"40485171","id":"PMC_40485171","title":"Direct scavenging of ROS by S-PPE NP reduces oxidative stress-induced stimulation of the SESN2/AMPK/KIM-1 pathway in acute kidney injury.","date":"2025","source":"Renal failure","url":"https://pubmed.ncbi.nlm.nih.gov/40485171","citation_count":1,"is_preprint":false},{"pmid":"38477077","id":"PMC_38477077","title":"Lysine specific demethylase 1 inhibits sodium arsenite activation of HSCs by regulating SESN2/AMPK/ULK1 signaling pathway activity.","date":"2024","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38477077","citation_count":1,"is_preprint":false},{"pmid":"41351982","id":"PMC_41351982","title":"Rhoifolin prevents herpes simplex virus encephalitis by modulating SESN2 to regulate the Keap1/Nrf2 and AMPK/Nox pathways to inhibit neuro-oxidative damage in mice.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41351982","citation_count":1,"is_preprint":false},{"pmid":"41086475","id":"PMC_41086475","title":"Polylactic acid microplastics and fish species intestinal inflammation risk: Associated with mitochondrial function mediated by Sesn2/Nrf2 pathway.","date":"2025","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/41086475","citation_count":1,"is_preprint":false},{"pmid":"32511948","id":"PMC_32511948","title":"WITHDRAWN: GAS5 enhances natural killer cell-mediated killing by promoting ubiquitination of SESN2 in prostate cancer cells.","date":"2020","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32511948","citation_count":1,"is_preprint":false},{"pmid":"40425138","id":"PMC_40425138","title":"SESN2 mediates resistance training-induced improvements in exercise performance and energy metabolism in C57BL/6J mice.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40425138","citation_count":0,"is_preprint":false},{"pmid":"39417977","id":"PMC_39417977","title":"SESN2 Ameliorates Dihydrotestosterone-induced Human Ovarian Granulosa Cell Damage by Activating AMPK/ULK1-mediated Mitophagy.","date":"2024","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39417977","citation_count":0,"is_preprint":false},{"pmid":"41196342","id":"PMC_41196342","title":"A viral Cyclin D homolog protein hijacks the metabolic stress sensor SESN2 to promote primary effusion lymphoma growth.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41196342","citation_count":0,"is_preprint":false},{"pmid":"41383119","id":"PMC_41383119","title":"Mesenchymal stromal cells preserve alveolar macrophages by inducing Sesn2 expression via lactic acid production in a mouse model of bleomycin-induced lung injury.","date":"2025","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/41383119","citation_count":0,"is_preprint":false},{"pmid":"40374019","id":"PMC_40374019","title":"Zinc finger transcription factor ZNF384 mitigates LPS-induced ferroptosis and inflammation in lung epithelial cells by activating SESN2-mediated autophagy.","date":"2025","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/40374019","citation_count":0,"is_preprint":false},{"pmid":"41527177","id":"PMC_41527177","title":"Inhibitory effect of blestriarene C on triple-negative breast cancer: Inducing ferroptosis and mitophagy via SESN2/AKT/FOXO4 axis.","date":"2026","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/41527177","citation_count":0,"is_preprint":false},{"pmid":"41370333","id":"PMC_41370333","title":"Protective Effect of SESN2 on Glutamate Neurotoxicity via Keap1-Nrf2 Pathway-Mediated Mitophagy.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41370333","citation_count":0,"is_preprint":false},{"pmid":"42110337","id":"PMC_42110337","title":"The FOXM1-SESN2 axis maintains redox homeostasis and protects esophageal squamous carcinoma cells from oxidative stress.","date":"2026","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/42110337","citation_count":0,"is_preprint":false},{"pmid":"41966311","id":"PMC_41966311","title":"SESN2 suppresses ferroptosis in polycystic ovary syndrome by maintaining PRDX6 K209 lactylation.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41966311","citation_count":0,"is_preprint":false},{"pmid":"42105713","id":"PMC_42105713","title":"Yakuchinone A alleviates hepatic ischemia-reperfusion injury in aging livers via the SESN2/AKT1/NRF2 pathway.","date":"2026","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42105713","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56545,"output_tokens":8248,"usd":0.146677,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17705,"output_tokens":4855,"usd":0.10495,"stage2_stop_reason":"end_turn"},"total_usd":0.251627,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"SESN2 (Hi95) is a stress-responsive gene transcriptionally induced by prolonged hypoxia, DNA damage (in a p53-dependent manner), and oxidative stress (p53-independent). Overexpression is toxic to many cell types, causing apoptosis or sensitization to stress, but conditional overexpression in MCF7 cells protects against hypoxia/glucose deprivation and H2O2-induced cell death.\",\n      \"method\": \"cDNA microarray, conditional overexpression (tet-off system), cell viability assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple expression and overexpression experiments, but no molecular partner identification or pathway reconstitution\",\n      \"pmids\": [\"12203114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SESN2 suppresses prolonged NLRP3 inflammasome activation by inducing mitophagy in macrophages. Mechanistically, SESN2 (1) facilitates perinuclear clustering of mitochondria by mediating SQSTM1 aggregation and its binding to K63-linked ubiquitins on the mitochondrial surface ('mitochondrial priming'), and (2) activates autophagic machinery by increasing ULK1 protein levels. SESN2 expression in macrophages is induced by NOS2-derived NO. Sesn2-deficient mice show defective mitophagy and hyperactivation of inflammasomes with increased mortality in two sepsis models.\",\n      \"method\": \"Genetic knockout mice (two sepsis models), siRNA knockdown, immunofluorescence, co-immunoprecipitation, Western blot, ubiquitin binding assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal mechanistic experiments in macrophages and in vivo knockout models with multiple orthogonal methods, replicated in two sepsis models\",\n      \"pmids\": [\"27337507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SESN2 expression is transcriptionally induced by ISO treatment via a MAPK8/JNK1-JUN-dependent mechanism: ISO triggers MAPK8-dependent JUN activation and JUN binding to an AP-1 site in the SESN2 promoter, leading to SESN2 transcriptional induction that is required for autophagy induction in bladder cancer cells.\",\n      \"method\": \"Promoter-binding (ChIP/AP-1 reporter), siRNA knockdown, kinase inhibitors, Western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing JUN binding to SESN2 promoter plus loss-of-function, single lab\",\n      \"pmids\": [\"27171279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UVB induces SESN2 expression in melanocytes through the p53 and AKT3 pathways; SESN2 negatively regulates UVB-induced DNA damage repair. UVA induces SESN2 through mitochondria (not Nrf2); SESN2 ablation increased UVA-induced Nrf2 induction and inhibited UVA-induced ROS production, identifying SESN2 as an upstream regulator of Nrf2.\",\n      \"method\": \"siRNA knockdown, pathway inhibitors, ROS measurement, DNA damage assays, immunoblot\",\n      \"journal\": \"Photochemistry and photobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway readouts, single lab, two orthogonal UV stimuli\",\n      \"pmids\": [\"27463837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LSD1/KDM1A epigenetically represses SESN2 transcription by binding to its promoter. Pharmacological inhibition or selective ablation of LSD1 de-represses SESN2 expression, which then inhibits mTORC1 activity and promotes autophagy in neuroblastoma cells. SESN2 overexpression alone suffices to promote autophagy, and SESN2 loss reduces LSD1 inhibition-induced autophagy.\",\n      \"method\": \"ChIP (LSD1 binding to SESN2 promoter), LSD1 inhibitors (TCP, SP2509), siRNA/shRNA knockdown, mTORC1 activity assays, autophagy assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus pharmacological and genetic loss-of-function with multiple mechanistic readouts, consistent epistatic placement\",\n      \"pmids\": [\"28783174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SESN2 facilitates Parkin translocation to defective mitochondria during mitophagy by interacting with ULK1 and assisting ULK1-mediated phosphorylation of Beclin1 at serine-14, which is required for Beclin1-Parkin binding prior to mitochondrial translocation. The trigger for SESN2 activation is mitochondrial superoxide. SESN2-mediated cytosolic Parkin-Beclin1 interaction is PINK1-independent, but mitochondrial translocation of Parkin is PINK1-dependent.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phosphorylation site mapping (S14-Beclin1), mitochondrial superoxide scavenging, mitophagy assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistatic dissection of PINK1-dependence, phosphorylation site identification, multiple orthogonal methods\",\n      \"pmids\": [\"29330382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBX1 is an E3 ubiquitin ligase for SESN2 that mediates K48-linked ubiquitination of SESN2 upon prolonged mitochondrial damage (CCCP treatment), leading to SESN2 degradation and increased cell death. Downregulation of RBX1 stabilizes SESN2, reduces mitochondrial ROS, and reduces cell death.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K48-linkage), siRNA knockdown, cell viability assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with K48 specificity, single lab\",\n      \"pmids\": [\"29294217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SESN2 negatively regulates mTORC1 activity in an amino acid-sensing context in cow mammary epithelial cells. Amino acid starvation increases SESN2 expression; SESN2 overexpression suppresses mTORC1 activation, cell proliferation, and casein synthesis; SESN2 inhibition reverses these effects.\",\n      \"method\": \"Overexpression and inhibition experiments, mTORC1 pathway readouts (Western blot), cell proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain and loss of function with multiple readouts, single lab; ortholog study consistent with mammalian SESN2 mechanism\",\n      \"pmids\": [\"29500367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BDNF promotes ATF4 elevation in neurons in a TrkB-dependent, eIF2α-independent manner. ATF4 then directly mediates BDNF-induced transcriptional induction of SESN2, establishing BDNF→TrkB→ATF4→SESN2 as a neuroprotective signaling axis.\",\n      \"method\": \"Transcriptome analysis, ATF4 knockdown, TrkB signaling inhibition, Western blot, neuronal cultures\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic + genetic epistasis (ATF4 KD abrogates SESN2 induction), single lab\",\n      \"pmids\": [\"29599707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SESN2 interacts with Parkin and p62/SQSTM1, promotes accumulation of Parkin to mitochondria, and thereby alleviates doxorubicin-caused inhibition of Parkin-mediated mitophagy. SESN2 knockout (by sgRNA) inhibits Parkin-mediated mitophagy, increases cardiomyocyte apoptosis, and worsens mitochondrial dysfunction; ectopic SESN2 expression rescues these effects.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR sgRNA knockout, mitophagy assays, electron microscopy, echocardiography, rat model\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of SESN2-Parkin-p62 complex, genetic KO and rescue in vivo and in vitro, multiple orthogonal methods\",\n      \"pmids\": [\"31199952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ER stress-induced CHOP transcription factor directly binds the SESN2 promoter in colorectal cancer cells, increasing SESN2 expression, which then promotes autophagy. DHA + oxaliplatin enhance CHOP binding to the SESN2 promoter.\",\n      \"method\": \"Chromatin immunoprecipitation (CHOP binding to SESN2 promoter), Western blot, autophagy assays, in vitro and in vivo\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating CHOP binding to SESN2 promoter, single lab, supported by functional autophagy readouts\",\n      \"pmids\": [\"31337142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SESN2 localizes to mitochondria, as demonstrated by subcellular fractionation and live-cell imaging experiments, and can directly regulate mitochondrial functions through mTORC1-independent mechanisms.\",\n      \"method\": \"Subcellular fractionation, mitochondrial localization experiments, live imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional implication, single lab\",\n      \"pmids\": [\"32287270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD3 histone demethylase negatively regulates SESN2 transcription by reducing H3K27me3 tri-methylation in the SESN2 promoter region. JMJD3 inhibition or knockdown restores SESN2 expression and protects against doxorubicin-induced cardiomyopathy; JMJD3 overexpression aggravates cardiomyopathy in a SESN2-dependent manner.\",\n      \"method\": \"ChIP (H3K27me3 at SESN2 promoter), JMJD3 knockdown/overexpression, SESN2 rescue overexpression, Western blot, cardiac functional assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating H3K27me3 reduction at SESN2 promoter by JMJD3, epistatic rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"33117796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SESN2 is transcriptionally induced by the ER stress-activated transcription factor C/EBPβ in denervated skeletal muscle. Once induced, SESN2 inhibits mTORC1 to attenuate ER stress, and also activates autophagic machinery to facilitate SQSTM1/p62 aggregation on the mitochondrial surface, promoting mitophagy and protecting against muscle atrophy.\",\n      \"method\": \"Knockdown and overexpression (AAV delivery), denervation mouse model, Western blot, electron microscopy, immunofluorescence, mTORC1 activity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown/overexpression in vivo, multiple pathway readouts, single lab\",\n      \"pmids\": [\"34429398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SESN2 promotes the formation of a complex between AMPK and LKB1 (as demonstrated by immunoprecipitation), thereby facilitating AMPK-T172 phosphorylation. This mechanism underlies globular adiponectin-induced AMPK activation and insulin sensitization in skeletal muscle; these effects are absent in SESN2-/- mice.\",\n      \"method\": \"Co-immunoprecipitation, SESN2 knockout mice, AMPK phosphorylation assays, insulin signaling readouts\",\n      \"journal\": \"Sports medicine and health science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating SESN2-AMPK-LKB1 complex, confirmed in KO mice, single lab\",\n      \"pmids\": [\"36994173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SESN2 inhibits mTORC1 activity through interaction with the GATOR2 protein complex, preventing GATOR2's inhibitory effect on GATOR1, which stimulates GTPase activity of RagA/B, preventing mTORC1 lysosomal translocation and activation. This pathway is established as SESN2's primary mTORC1-inhibitory mechanism.\",\n      \"method\": \"Pathway analysis, protein interaction (GATOR2/GATOR1/Rag GTPases), cited as established mechanism in review context within original research paper\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — described as established mechanism across multiple papers in the corpus including PMID:32287270; pathway placement is well-replicated across independent labs\",\n      \"pmids\": [\"32287270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SESN2 increases Nrf2 protein expression by enhancing p62-dependent autophagy in endothelial progenitor cells treated with angiotensin II, providing a mechanism linking SESN2 to antioxidant defense via the Keap1/Nrf2 axis.\",\n      \"method\": \"Western blot, siRNA knockdown of Nrf2, p62 autophagy assays, immunofluorescence, EPCs from human umbilical cord blood\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mechanistic follow-up with siRNA and pathway readouts, single lab\",\n      \"pmids\": [\"33231566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PERK pathway upregulation increases SESN2 expression in porcine oocytes. SESN2 acts upstream of NRF2: SESN2 siRNA knockdown blocks NRF2 nuclear activation, while NRF2 inhibition does not affect SESN2 protein levels. SESN2 deficiency blocks nuclear NRF2 activity and disrupts spindle assembly during oocyte maturation.\",\n      \"method\": \"siRNA knockdown, Western blot, immunofluorescence, NRF2 inhibitor, porcine oocyte IVM\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic relationship established by siRNA and pharmacological inhibition with pathway directionality confirmed, single lab\",\n      \"pmids\": [\"34923100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UPRmt upregulates SESN2 through the Eif2ak4/eIF2α/Atf4 transcriptional axis. SESN2 then promotes translocation of cytosolic Parkin and SQSTM1 to defective mitochondria using two functional domains required for interacting with Parkin and SQSTM1, respectively. SQSTM1 translocation to mitochondria is Parkin-dependent. SESN2-mediated cytosolic Parkin-SQSTM1 interaction is PINK1-independent, while mitochondrial translocation requires PINK1.\",\n      \"method\": \"siRNA/gene silencing, domain mutagenesis, co-immunoprecipitation, Sesn2-/- mice (intervertebral disc degeneration model), mitophagy assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis identifying SESN2 interaction domains, PINK1 epistasis, Sesn2-/- in vivo model, replicates and extends PMID:29330382\",\n      \"pmids\": [\"36632468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"p53-regulated SESN2 suppresses STAT3 activity by downregulating the PTPRD phosphatase (responsible for STAT3 dephosphorylation), thereby regulating cell proliferation and death via an mTORC1-independent mechanism. SESN1&2 inactivation in A549 cells accelerates proliferation and confers drug resistance without affecting mTORC1, but stimulates STAT3.\",\n      \"method\": \"SESN1&2 double inactivation in A549 cells, STAT3 phosphorylation assays, PTPRD expression analysis, cell proliferation and death assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic inactivation with mechanistic epistasis (PTPRD→STAT3), single lab, novel mechanism\",\n      \"pmids\": [\"39985075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Melatonin-induced SESN2 inhibits hepatic gluconeogenesis via a SESN2-SHP signaling cascade that competes with BTG2 and inhibits CREBH-mediated gluconeogenic gene transcription, suppressing the CRBN-BTG2-CREBH signaling axis.\",\n      \"method\": \"Sesn2 and Shp silencing mice, primary hepatocytes, gene expression analysis, rescue experiments\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic silencing in vivo and in vitro with mechanistic epistasis, single lab\",\n      \"pmids\": [\"37488285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FTO demethylase reduces m6A methylation of SESN2 mRNA, decreasing its stability. FTO deficiency promotes binding of IGF2BP1 to SESN2 mRNA at exon 9 m6A modification sites, enhancing SESN2 mRNA stability and elevating SESN2 protein expression, which activates AMPK-mTOR-dependent autophagy in NSCLC cells.\",\n      \"method\": \"m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA stability assays, IGF2BP1 RIP, site-specific m6A mapping, SESN2 knockdown\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq with mechanistic follow-up on mRNA stability via IGF2BP1, single lab\",\n      \"pmids\": [\"38495179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SETDB1 histone methyltransferase collaborates with heterochromatin protein HP1β to deposit H3K9me3 on the SESN2 promoter, thereby repressing SESN2 expression. SESN2 mediates SETDB1's regulation of mitochondrial damage and oxidative stress in renal ischemia-reperfusion injury.\",\n      \"method\": \"ChIP (H3K9me3 at SESN2 promoter), co-immunoprecipitation (SETDB1-HP1β), SETDB1 knockdown and pharmacological inhibition, in vivo and in vitro I/R models\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating H3K9me3 at SESN2 promoter, Co-IP of SETDB1-HP1β complex, rescue experiments in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"39443993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SESN2 promotes the interaction between SESN2 and RPN2 (ribophorin II) in response to leucine binding. RPN2 overexpression activates the GSK3β/β-catenin pathway (increasing nuclear β-catenin), whereas RPN2 knockdown combined with leucine rescues GSK3β phosphorylation effects, supporting SESN2-mediated promotion of C2C12 myoblast differentiation via the GSK3β/β-catenin pathway.\",\n      \"method\": \"Co-immunoprecipitation (SESN2-RPN2 interaction), RPN2 overexpression and knockdown, RNA sequencing, Western blot, β-catenin nuclear translocation assays, in vivo muscle injury model\",\n      \"journal\": \"Journal of the science of food and agriculture\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating SESN2-RPN2 interaction, epistatic rescue experiments, single lab\",\n      \"pmids\": [\"38551359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SESN2 knockdown in brain tissue increases mTOR/HIF-1α pathway activity and enhances glycolysis (increased HK2, PFKM, PKM1, PKM2, GLUT1, and lactate levels), worsening cerebral ischemia-reperfusion injury. mTOR inhibition with rapamycin reverses these effects, demonstrating that SESN2 regulates glycolysis via mTOR/HIF-1α.\",\n      \"method\": \"Lentiviral SESN2 shRNA knockdown, MCAO mouse model, rapamycin rescue, Western blot, immunofluorescence, lactate assay\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic knockdown with rapamycin rescue establishes epistatic pathway, single lab\",\n      \"pmids\": [\"40032632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KSHV-encoded vCyclin (a Cyclin D homolog) directly interacts with SESN2 and recruits the deubiquitinase OTUB1, blocking SESN2 polyubiquitination and proteasomal degradation, thereby stabilizing and upregulating SESN2. vCyclin lysine at residue 74 is crucial for cytosolic localization, OTUB1 recruitment, and SESN2 upregulation. Stabilized SESN2 activates AMPK to support survival of KSHV-driven primary effusion lymphoma cells.\",\n      \"method\": \"Co-immunoprecipitation (vCyclin-SESN2-OTUB1 complex), site-directed mutagenesis (K74 of vCyclin), ubiquitination assays, AMPK activity assays, cell survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of key residue, ubiquitination assays, functional downstream readout, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"41196342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SESN2 directly binds AKT1 and promotes its phosphorylation at Ser473, which activates NRF2 nuclear localization to inhibit ferroptosis. Hepatocyte-specific AAV-mediated SESN2 knockdown abolishes the hepatoprotective effects of Yakuchinone A, establishing SESN2 as its primary pharmacological target in hepatic ischemia-reperfusion injury.\",\n      \"method\": \"AAV-mediated hepatocyte-specific overexpression/knockdown in vivo, co-immunoprecipitation (SESN2-AKT1), AKT1 phosphorylation assays, NRF2 nuclear translocation, rescue-of-function experiments\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vivo genetic rescue, single lab, novel physical interaction claim\",\n      \"pmids\": [\"42105713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SESN2 interacts with SCAP (SREBP cleavage-activating protein) to deactivate SREBP1-mediated transcription of lipogenic enzymes in chondrocytes, and overexpression of Sesn2 in mice prevents obesity-related cartilage lipogenesis and OA progression.\",\n      \"method\": \"Co-immunoprecipitation (SESN2-SCAP), SREBP1 target gene assays, AAV-mediated Sesn2 overexpression in DMM mouse model, Western blot, histology\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of SESN2-SCAP, in vivo overexpression rescue, single lab\",\n      \"pmids\": [\"40822351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SESN2 deficiency reduces PRDX6 K209 lactylation, a modification required for PRDX6-mediated redox homeostasis; quantitative co-immunoprecipitation showed PRDX6 interacts with GPX4, and this interaction is markedly weakened by K209R mutation. Re-expression of wild-type PRDX6 but not K209R mutant rescues SESN2 deficiency-induced oxidative stress and ferroptosis in granulosa cells.\",\n      \"method\": \"Quantitative co-immunoprecipitation, site-directed mutagenesis (K209R), lactylation analysis, SESN2 deficiency models (in vitro/in vivo), rescue experiments\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, and rescue experiments establishing SESN2-PRDX6-GPX4 axis, single lab\",\n      \"pmids\": [\"41966311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SESN2 overexpression promotes MVB (multivesicular body) degradation by inhibiting Rab-7a ubiquitination, thereby promoting autophagosome-lysosome fusion. Additionally, SESN2 promotes TFEB nuclear translocation via the mTOR pathway to enhance lysosomal function, reducing exosome secretion from BSA-injured tubular cells.\",\n      \"method\": \"RNA-seq, IP-MS, Western blot, TFEB nuclear translocation assay, Rab-7a ubiquitination assay, SESN2 overexpression in HK2 cells\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS and ubiquitination assay, TFEB nuclear translocation readout, single lab\",\n      \"pmids\": [\"40612680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-182-5p directly represses SESN2 expression by targeting its 3'-UTR (validated by luciferase reporter and RNP-IP), and ATO-mediated suppression of miR-182-5p leads to stabilization of SESN2 mRNA through AGO2-dependent gene silencing relief.\",\n      \"method\": \"Luciferase reporter assay (SESN2 3'UTR), ribonucleoprotein immunoprecipitation (RNP-IP/AGO2), miR-182-5p mimic transfection, mRNA stability assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus RNP-IP demonstrating AGO2-dependent silencing of SESN2 mRNA, single lab\",\n      \"pmids\": [\"29662624\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SESN2 is a p53-regulated, stress-inducible protein that inhibits mTORC1 by binding GATOR2 (disrupting GATOR1 inhibition and thereby suppressing RagA/B-dependent mTORC1 lysosomal recruitment), promotes mitophagy by facilitating ULK1-mediated Beclin1-S14 phosphorylation and Parkin/SQSTM1 translocation to damaged mitochondria (via two distinct SESN2 functional domains), is post-translationally regulated by K48-linked ubiquitination through RBX1 and stabilized by KSHV vCyclin/OTUB1-mediated deubiquitination, is transcriptionally controlled by p53, C/EBPβ, ATF4/CHOP, and epigenetically repressed by LSD1 (H3K4me2) and JMJD3/SETDB1 (H3K27me3/H3K9me3), acts upstream of Nrf2 to regulate ROS, suppresses STAT3 by maintaining PTPRD phosphatase levels, interacts with SCAP to inhibit SREBP1-mediated lipogenesis, binds AKT1 to promote its Ser473 phosphorylation, and localizes to mitochondria to regulate mitochondrial function independently of mTORC1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SESN2 is a stress-inducible cytoprotective protein that integrates signals from hypoxia, DNA damage, oxidative stress, ER stress, and nutrient deprivation to restrain mTORC1 signaling and promote autophagy/mitophagy [#0, #4, #13]. Its principal anabolic-restraining function is inhibition of mTORC1: SESN2 binds the GATOR2 complex, relieving GATOR2 suppression of GATOR1, which stimulates RagA/B GTPase activity and prevents lysosomal recruitment/activation of mTORC1 in amino-acid- and stress-sensing contexts [#15, #7]. Independently of mTORC1, SESN2 drives selective clearance of damaged mitochondria: triggered by mitochondrial superoxide, it interacts with ULK1 to elevate ULK1 levels and promote ULK1-mediated phosphorylation of Beclin1 at Ser14, enabling cytosolic Parkin–Beclin1/SQSTM1 assembly and PINK1-dependent translocation of Parkin and SQSTM1 to damaged mitochondria via two distinct functional domains [#5, #18, #1, #9]. Through these activities SESN2 suppresses prolonged NLRP3 inflammasome activation and protects against tissue injury in sepsis, cardiomyopathy, and disc degeneration [#1, #9, #18]. SESN2 also acts upstream of the NRF2 antioxidant program—enhancing NRF2 via p62-dependent autophagy and AKT1-Ser473 phosphorylation—and limits ferroptosis and ROS [#3, #16, #17, #26]. Beyond redox and autophagy control, SESN2 restrains lipogenesis by binding SCAP to block SREBP1 activation [#27], suppresses STAT3 by maintaining the phosphatase PTPRD [#19], and regulates AMPK activation by promoting AMPK–LKB1 complex formation [#14]. SESN2 expression is tightly controlled: it is transcriptionally induced by p53, ATF4/CHOP, C/EBPβ, and JUN [#0, #8, #10, #13, #2]; epigenetically repressed by LSD1, JMJD3, and SETDB1/HP1β at its promoter [#4, #12, #22]; post-transcriptionally regulated by miR-182-5p and FTO/IGF2BP1-dependent m6A control [#30, #21]; and stabilized or degraded through K48-linked ubiquitination by RBX1 versus deubiquitination by OTUB1, the latter exploited by KSHV vCyclin to sustain AMPK-driven lymphoma survival [#6, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SESN2 as a stress-responsive gene, defining the inducing signals (hypoxia, p53-dependent DNA damage, p53-independent oxidative stress) and its context-dependent role in cell death versus protection.\",\n      \"evidence\": \"cDNA microarray and conditional (tet-off) overexpression with viability assays\",\n      \"pmids\": [\"12203114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner or pathway mechanism identified\", \"Pro-death versus pro-survival switch unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined SESN2 as a driver of mitophagy that limits inflammation, linking it mechanistically to SQSTM1-mediated mitochondrial priming and ULK1 upregulation in vivo.\",\n      \"evidence\": \"Sesn2-knockout mice in two sepsis models, Co-IP, ubiquitin-binding assays, and imaging in macrophages\",\n      \"pmids\": [\"27337507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain mediating SQSTM1/ubiquitin engagement not mapped\", \"Mechanism of ULK1 protein-level increase unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the JNK/JUN-AP1 axis and the p53/AKT3 and mitochondrial routes as distinct upstream inducers of SESN2, expanding the transcriptional input map and placing SESN2 upstream of Nrf2.\",\n      \"evidence\": \"ChIP/AP-1 reporter, kinase inhibitors, siRNA, ROS and DNA-damage assays across stimuli\",\n      \"pmids\": [\"27171279\", \"27463837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SESN2 negatively regulates DNA-damage repair is unclear\", \"Molecular link from SESN2 to Nrf2 not yet defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed SESN2 within an epigenetic repression circuit, showing LSD1 (H3K4me2) at the promoter restrains SESN2-driven mTORC1 inhibition and autophagy.\",\n      \"evidence\": \"ChIP, LSD1 inhibitors/knockdown, mTORC1 and autophagy readouts in neuroblastoma\",\n      \"pmids\": [\"28783174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors recruiting LSD1 to the SESN2 promoter unidentified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the molecular mechanism of SESN2-driven mitophagy: ULK1 interaction and Beclin1-S14 phosphorylation gate cytosolic Parkin assembly (PINK1-independent) prior to PINK1-dependent mitochondrial translocation.\",\n      \"evidence\": \"Reciprocal Co-IP, phosphosite mapping, superoxide scavenging, PINK1 epistasis\",\n      \"pmids\": [\"29330382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase/substrate biochemistry of the SESN2-ULK1-Beclin1 step not reconstituted\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined post-translational and additional transcriptional control of SESN2, identifying RBX1 as a K48-linked E3 ligase driving SESN2 degradation, ATF4 as a BDNF/TrkB-driven inducer, and amino-acid-sensitive mTORC1 suppression.\",\n      \"evidence\": \"Co-IP/ubiquitination assays, transcriptome and ATF4 knockdown, gain/loss-of-function mTORC1 readouts\",\n      \"pmids\": [\"29294217\", \"29599707\", \"29500367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RBX1 partner cullin/adaptor not defined\", \"Degron on SESN2 not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed the SESN2-Parkin-SQSTM1 mitophagy module in cardiac tissue and extended it to CHOP-driven transcriptional induction under ER stress, linking SESN2 to autophagic cytoprotection.\",\n      \"evidence\": \"Co-IP, CRISPR KO and rescue in rat cardiac model; ChIP of CHOP at SESN2 promoter\",\n      \"pmids\": [\"31199952\", \"31337142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SESN2-Parkin binding is direct unresolved\", \"Quantitative contribution of CHOP versus other TFs not parsed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated mitochondrial localization of SESN2 and mTORC1-independent regulation of mitochondrial function, and consolidated the GATOR2-GATOR1-Rag mechanism as the primary mTORC1-inhibitory route.\",\n      \"evidence\": \"Subcellular fractionation and live imaging; pathway analysis of GATOR2/GATOR1/Rag interactions\",\n      \"pmids\": [\"32287270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial submembrane location and import mechanism unknown\", \"Direct structural basis of SESN2-GATOR2 binding not shown in these data\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened SESN2 regulatory inputs and outputs: C/EBPβ induction in atrophying muscle, AMPK-LKB1 complex promotion, p62-dependent NRF2 elevation, PERK-driven NRF2 epistasis, and JMJD3-mediated H3K27me3 repression.\",\n      \"evidence\": \"In vivo knockdown/overexpression, Co-IP, ChIP, siRNA/inhibitor epistasis across muscle, endothelial, and oocyte systems\",\n      \"pmids\": [\"34429398\", \"36994173\", \"33231566\", \"34923100\", \"33117796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SESN2-AMPK-LKB1 contact is direct unresolved\", \"Stoichiometry and selectivity of SESN2 toward distinct effectors unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified domain-level and effector-level specificity: two SESN2 domains separately engage Parkin and SQSTM1 for UPRmt-induced mitophagy, while mTORC1-independent branches act through PTPRD-STAT3, SHP-CREBH gluconeogenesis control, m6A/IGF2BP1 mRNA stabilization, and Rab7a/TFEB-dependent lysosomal trafficking.\",\n      \"evidence\": \"Domain mutagenesis, PINK1 epistasis, Sesn2-/- models, genetic inactivation, MeRIP-seq, IP-MS, ubiquitination and TFEB translocation assays\",\n      \"pmids\": [\"36632468\", \"39985075\", \"37488285\", \"38495179\", \"40612680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Boundaries and structures of the two functional domains not defined\", \"How SESN2 lowers PTPRD mechanistically unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended SESN2 control of metabolism and redox: SETDB1/HP1β-mediated H3K9me3 repression, mTOR/HIF-1α-dependent glycolytic restraint, and leucine-induced SESN2-RPN2 signaling to GSK3β/β-catenin in myogenesis.\",\n      \"evidence\": \"ChIP, Co-IP, knockdown/inhibitor and rapamycin rescue in renal I/R, MCAO, and myoblast models\",\n      \"pmids\": [\"39443993\", \"40032632\", \"38551359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SESN2-RPN2 functional consequence on leucine sensing unclear\", \"Connection between mitochondrial SESN2 and glycolytic output incompletely defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved deubiquitinase-mediated stabilization and new direct interactors: KSHV vCyclin/OTUB1 stabilizes SESN2 to drive AMPK and lymphoma survival, SESN2 binds AKT1 to drive Ser473 phosphorylation and NRF2-dependent anti-ferroptosis, binds SCAP to block SREBP1 lipogenesis, and supports PRDX6-K209 lactylation/GPX4 redox defense.\",\n      \"evidence\": \"Reciprocal Co-IP, residue mutagenesis (vCyclin K74, PRDX6 K209R), ubiquitination and AKT1 phosphorylation assays, AAV in vivo rescue\",\n      \"pmids\": [\"41196342\", \"42105713\", \"40822351\", \"41966311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SESN2-AKT1 binding directly catalyzes Ser473 phosphorylation versus scaffolding unresolved\", \"Structural basis of SESN2-SCAP interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single SESN2 protein selects among its many described effectors (GATOR2, ULK1/Parkin, AKT1, SCAP, AMPK-LKB1, RPN2) in a given cell state, and the structural basis for these competing interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model distinguishing the effector-binding surfaces\", \"Determinants of mitochondrial versus cytosolic SESN2 partitioning unknown\", \"Quantitative hierarchy among parallel SESN2 outputs not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 18, 14]},\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [3, 16, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11, 5, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 5, 18, 9]},\n      {\"term_id\": \"R-HSA-165159\", \"supporting_discovery_ids\": [15, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 3, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [20, 24, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GATOR2\", \"ULK1\", \"Parkin\", \"SQSTM1\", \"SCAP\", \"AKT1\", \"RPN2\", \"SETDB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}