{"gene":"SREBF2","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1993,"finding":"SREBP-2 is a bHLH-Zip transcription factor that binds sterol regulatory element 1 (SRE-1) and activates transcription of genes controlling cholesterol synthesis and uptake; it contains an acidic NH2-terminal transactivation domain, a conserved bHLH-Zip motif, and a long COOH-terminal regulatory domain. In vitro DNA binding and in vivo reporter assays demonstrated SRE-1 binding specificity and transcriptional activation capacity.","method":"cDNA cloning, in vitro DNA binding assay, cotransfection reporter assay in HEK293 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original reconstitution of DNA-binding and transactivation with multiple orthogonal methods; foundational paper with 544 citations","pmids":["7903453"],"is_preprint":false},{"year":1996,"finding":"SREBP-2 is released from the endoplasmic reticulum membrane by two sequential proteolytic cleavages: the first, sterol-regulated, occurs in the lumenal loop between the two transmembrane segments; the second, sterol-independent, occurs within the first transmembrane domain. The liberated NH2-terminal transcription factor domain then enters the nucleus to activate cholesterol biosynthesis and uptake genes.","method":"H-Ras-SREBP-2 fusion protein expression, mutant CHO cell analysis, cell fractionation, transcriptional reporter assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with defined mutants and fusion proteins; mechanistic cleavage pathway established; 462 citations","pmids":["8674110"],"is_preprint":false},{"year":1997,"finding":"The SREBF2 gene spans 72 kb and is composed of 19 exons and 18 introns; a perfect 10-bp SRE-1 sequence is present in the SREBF2 promoter, providing a mechanism for autoregulation of its own transcription by sterol levels.","method":"Genomic cloning, sequencing, 5'-flanking region analysis, transcription start site mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — direct structural determination of gene, replicated SRE-1 identification","pmids":["9070916"],"is_preprint":false},{"year":2004,"finding":"ATF6 N-terminal fragment (ATF6(N)) directly binds to SREBP-2 N-terminal fragment (SREBP2(N)) through its leucine-zipper domain; the ATF6-SREBP-2 complex recruits HDAC1 to SRE-bound SREBP-2, attenuating SREBP-2 transcriptional activity and suppressing lipogenesis in liver cells.","method":"GST pull-down, co-immunoprecipitation, deletion mutagenesis, chromatin immunoprecipitation (ChIP), reporter assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (GST pull-down, Co-IP, ChIP, reporter assay) in single study","pmids":["14765107"],"is_preprint":false},{"year":2003,"finding":"SREBP-2 directly activates transcription of the IDH1 (cytosolic NADP-dependent isocitrate dehydrogenase) gene by binding to a specific SRE sequence (GTGGGCTGAG) in the IDH1 promoter, linking cholesterol/fatty acid biosynthetic regulation to NADPH generation.","method":"Promoter-reporter assays, electrophoretic mobility shift assay (EMSA), mutagenesis, sterol-depletion experiments","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 — direct DNA binding demonstrated by EMSA and mutagenesis with functional reporter validation","pmids":["12923220"],"is_preprint":false},{"year":2010,"finding":"The primary transcript of SREBF2 contains an intronic miRNA (miR-33a) that reduces cellular cholesterol export by inhibiting translation of ABCA1, and also inhibits fatty acid β-oxidation by suppressing CPT1A, HADHB, and CROT, functionally coupling cholesterol synthesis promotion with prevention of cholesterol export and lipid degradation.","method":"Identification of miRNA within SREBF2 intron, transfection-based translation inhibition assays, functional cholesterol export and FAO assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — original discovery with multiple functional readouts; replicated widely (303 citations)","pmids":["20732877"],"is_preprint":false},{"year":2013,"finding":"FoxO3 recruits Sirt6 to the Srebp2 gene promoter, where Sirt6 deacetylates histone H3 at lysines 9 and 56 to promote a repressive chromatin state, thereby reducing hepatic SREBP-2 expression and cholesterol biosynthesis. Hepatic Sirt6 deficiency elevates cholesterol levels, and Sirt6 or FoxO3 overexpression improves hypercholesterolemia in obese mice.","method":"Hepatic Sirt6 knockout mice, chromatin immunoprecipitation, overexpression in vivo, cholesterol measurement","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — genetic KO + ChIP + in vivo rescue; multiple orthogonal methods","pmids":["23881913"],"is_preprint":false},{"year":2015,"finding":"SREBP-2 directly binds to an SREBP-2-binding element in the 5'-flanking c-Myc promoter region and drives c-Myc transcriptional activation, inducing cancer stem cell-like properties and metastasis in prostate cancer cells.","method":"Chromatin immunoprecipitation, promoter reporter assay, SREBP-2 overexpression/knockdown with functional assays (proliferation, invasion, prostasphere, xenograft)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter plus functional phenotype, single lab","pmids":["26883200"],"is_preprint":false},{"year":2016,"finding":"SREBP-2 directly induces transcription of the long-chain acyl-CoA synthetase 1 (ACSL1) C-transcript via a specific SRE motif in the ACSL1 C-promoter; knockdown of endogenous SREBP-2 in HepG2 cells reduces ACSL1 expression, linking cholesterol-sensing SREBP-2 to fatty acid activation.","method":"Promoter activity assay, DNA binding assay (EMSA), SREBP-2 knockdown, statin treatment in hamsters and mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — promoter assay + EMSA mutagenesis + siRNA knockdown; multiple orthogonal methods in one study","pmids":["26728456"],"is_preprint":false},{"year":2009,"finding":"SREBP-1 and SREBP-2 directly bind the proximal promoter region of the CASP7 gene (encoding caspase 7) as demonstrated by chromatin immunoprecipitation, and knockdown of SREBP-1/2 strongly reduces caspase 7 mRNA and protein expression, identifying CASP7 as a direct SREBP target.","method":"ChIP, siRNA knockdown, quantitative PCR, Western blot","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus siRNA knockdown with defined phenotype, single lab","pmids":["19323650"],"is_preprint":false},{"year":2010,"finding":"SREBP-2 directly regulates NPC1L1 promoter activity in a dose-dependent manner and binds to the NPC1L1 promoter in vivo; overexpression of active SREBP-2 protects NPC1L1 from inhibitory effects, establishing NPC1L1 as a direct SREBP-2 target gene in human liver.","method":"Luciferase promoter assay, ChIP, SREBP-2 overexpression, correlation analysis in human liver biopsies","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP confirms in vivo binding, reporter and overexpression rescue; multiple methods","pmids":["20460578"],"is_preprint":false},{"year":2011,"finding":"Curcumin reduces SREBP-2 DNA-binding activity and nuclear translocation partly through AMPK activation, thereby suppressing NPC1L1 promoter activity and cholesterol absorption; overexpression of active SREBP-2 rescues NPC1L1 from curcumin inhibition, demonstrating SREBP-2 mediates NPC1L1 regulation.","method":"Reporter assay, Western blot, AMPK activation measurement, SREBP-2 overexpression rescue, EMSA","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter + rescue + EMSA; single lab","pmids":["21527728"],"is_preprint":false},{"year":2012,"finding":"Oligomeric Aβ42 inhibits SREBP-2 proteolytic cleavage in neurons, causing decreased protein prenylation and cholesterol sequestration; supplying geranylgeranyl pyrophosphate to Aβ-treated neurons restores prenylation, reduces cholesterol sequestration, and prevents neurotoxicity, identifying SREBP-2 as a target of Aβ neurotoxicity.","method":"Intracellular Aβ42 delivery, SREBP-2 cleavage assay (Western blot), prenylation assays, isoprenoid supplementation rescue, cortex analysis in TgCRND8 mice","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic rescue experiments and in vivo validation; single lab","pmids":["22573671"],"is_preprint":false},{"year":2013,"finding":"TLR4-MyD88-NF-κB signaling increases SCAP expression and promotes abnormal SCAP translocation from the ER to the Golgi, activating the SCAP-SREBP-2 pathway to upregulate LDLR and HMG-CoAR expression and drive macrophage foam cell formation; MyD88 knockdown or IKK inhibition blocks these effects.","method":"siRNA knockdown, Western blot, RT-PCR, immunofluorescence/confocal microscopy, cholesterol measurement in THP-1 macrophages","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA epistasis plus organelle localization imaging; single lab","pmids":["23335792"],"is_preprint":false},{"year":2014,"finding":"PP2A directly interacts with nuclear SREBP-2 in response to cholesterol depletion, alters its phosphorylation state, and promotes SREBP-2 DNA binding to the LDLR SRE promoter element, increasing LDLR expression and LDL uptake; PP2A inhibition or depletion by okadaic acid/siRNA abolishes SREBP-2 binding without affecting cleavage or nuclear translocation.","method":"Co-immunoprecipitation, siRNA knockdown, okadaic acid inhibition, ChIP/DNA binding assay, LDL uptake assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct physical interaction (Co-IP) + functional epistasis (siRNA) + DNA binding assay; multiple orthogonal methods","pmids":["24770487"],"is_preprint":false},{"year":2014,"finding":"Hepatic insulin receptor is required for normal SREBP-2 activation in response to feeding and statin treatment; LIRKO mice lacking liver insulin receptors show suppressed SREBP-2 and cholesterologenic gene expression, and the response of SREBP-2 to both fasting/refeeding and statin treatment is abolished, while ezetimibe (cholesterol absorption inhibitor) can still induce SREBP-2 in LIRKO livers.","method":"Liver insulin receptor knockout mice (LIRKO), gene expression microarray, Western blot, statin/ezetimibe treatment","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with multiple pharmacological epistasis experiments; well-controlled in vivo study","pmids":["24516236"],"is_preprint":false},{"year":2015,"finding":"ERBB4 activation by neuregulin-1 induces SREBP-2 cleavage and the appearance of mature SREBP-2 through a PI3K- and mTORC1/2-dependent (but AKT- and mTORC1-independent) pathway, increasing expression of cholesterol biosynthesis and LDL uptake genes; pharmacological inhibition of S1P protease blocks NRG1-induced cholesterol gene expression.","method":"ERBB4-ICD expression, NRG1 ligand stimulation, PI3K/mTOR inhibitor treatment, S1P protease inhibitor, immunoblot of cleaved SREBP-2, gene expression assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic dissection of pathway; single lab","pmids":["26535009"],"is_preprint":false},{"year":2015,"finding":"FXR activation in mice induces SREBP-2 gene transcription (via an FXR response element in intron 10 of Srebp-2) and increases miR-33 levels, but simultaneously induces INSIG-2A, which prevents SCAP-mediated SREBP-2 processing, thereby uncoupling miR-33 and SREBP-2 target gene programs.","method":"ChIP-seq (FXR response element identification), FXR agonist treatment in mice, Scap-/- epistasis, Western blot for precursor and nuclear SREBP-2, miR-33 quantification","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq + genetic epistasis in Scap-/- + multiple in vivo pharmacological experiments","pmids":["25593129"],"is_preprint":false},{"year":2015,"finding":"ITCH E3 ubiquitin ligase ubiquitinates SREBP-2, promoting its clearance; loss of ITCH reduces SREBP-2 ubiquitination and degradation, increasing nuclear SREBP-2 and LDLR expression, lowering circulating cholesterol. ITCH also ubiquitinates SIRT6 to promote its breakdown, reducing fatty acid oxidation.","method":"ApoE-/-ITCH-/- mouse model, bone marrow transplantation, ubiquitination assay, cholesterol measurement, gene expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO mouse model with ubiquitination mechanistic follow-up; single lab","pmids":["25777360"],"is_preprint":false},{"year":2015,"finding":"SREBP-2 deficiency causes embryonic lethality in mice, with surviving null mice showing alopecia, attenuated growth, and reduced adipose tissue; hypomorphic mice with low SREBP-2 have reduced hepatic cholesterol and nearly abolished liver SREBF1c transcripts, demonstrating SREBP-2 is required for SREBF1c expression in liver and for embryonic development.","method":"SREBP-2 knockout and hypomorphic mouse generation, gene expression analysis, cholesterol measurement, histology","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO/hypomorph models with tissue-specific phenotype characterization","pmids":["26685326"],"is_preprint":false},{"year":2020,"finding":"Ring finger protein 5 (RNF5), an ER-anchored E3 ubiquitin ligase, mediates Lys-29-linked polyubiquitination of SCAP at Lys-305 in cytosolic loop 2, enhancing the interaction between SCAP luminal loops 1 and 7 (a conformational change required for SCAP-SREBP-2 activation) and thereby activating SREBP-2 and cholesterol biosynthesis.","method":"siRNA knockdown, RNF5 overexpression, ubiquitination assay, K305R SCAP mutant in SCAP-deficient cells, co-immunoprecipitation, SREBP-2 target gene measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — site-specific mutagenesis + ubiquitination assay + conformational mechanistic insight; multiple orthogonal methods","pmids":["32054686"],"is_preprint":false},{"year":2020,"finding":"SREBP2 directly induces transcription of the iron carrier Transferrin (TF) gene in circulating melanoma cells, reducing intracellular iron pools, reactive oxygen species, and lipid peroxidation, thereby suppressing ferroptosis and conferring drug resistance.","method":"Single-cell RNA-seq, knockdown of SREBP2/TF, ferroptosis induction assays, lipid peroxidation measurement, xenograft tumor formation","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional induction with functional KD rescue; single lab, CTC model","pmids":["33203734"],"is_preprint":false},{"year":2021,"finding":"25-hydroxycholesterol (25-HC) produced by follicular dendritic cells directly restrains SREBP-2 activation in germinal center B cells; ectopic SREBP-2 expression drives rapid plasma cell differentiation, while SREBP-2 deficiency reduces plasma cell output, establishing a 25-HC-SREBP2 axis that shapes intestinal IgA responses.","method":"Ch25h-/- mouse model, B cell-specific SREBP-2 overexpression/deficiency, plasma cell differentiation assays, immunization and Salmonella infection models","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models (KO, overexpression, cell-type specific) with defined functional readouts","pmids":["34644558"],"is_preprint":false},{"year":2021,"finding":"Quaking (Qki) functions as a transcriptional co-activator of SREBP-2 in eye lens and oligodendrocytes by recruiting SREBP-2 and RNA polymerase II to promoter regions of cholesterol biosynthesis genes; Qki-deficient lens-specific mice show reduced cholesterol and progressive cataracts rescued by topical sterol administration.","method":"Lens-specific Qki knockout mice, transcriptome analysis, ChIP (SREBP-2 and Pol II), cholesterol measurement, sterol rescue experiment, direct DNA-binding assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP demonstrates co-recruitment of Qki and SREBP-2 to gene promoters; genetic KO with in vivo rescue","pmids":["34021134"],"is_preprint":false},{"year":2021,"finding":"Qki-5 acts as a transcriptional co-activator of SREBP-2 in oligodendrocytes to control cholesterol biosynthesis gene transcription required for myelinogenesis; Qki depletion in neural stem cells or OPCs impairs cholesterol biosynthesis and myelin assembly without blocking oligodendrocyte differentiation.","method":"Conditional Qki knockout in neural stem cells and OPCs, cholesterol measurement, transcriptome analysis, myelination phenotype assessment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined cellular and molecular phenotype, corroborating lens study (PMID 34021134)","pmids":["33942715"],"is_preprint":false},{"year":2022,"finding":"Caspase-3 (CASP3) mediates cleavage of SREBP-2 from the ER to promote cholesterol biosynthesis, which drives cancer stem cell expansion and resistance to sorafenib/lenvatinib via activation of the sonic hedgehog signaling pathway in hepatocellular carcinoma.","method":"Drug-resistant patient-derived xenografts, RNA-seq, CASP3 cleavage of SREBP-2 (Western blot), SREBP-2 loss-of-function, simvastatin treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic CASP3-cleavage identified + pathway epistasis; single lab","pmids":["35767704"],"is_preprint":false},{"year":2022,"finding":"Caffeine increases hepatic ER Ca2+ levels, which blocks SREBP-2 transcriptional activation (and thus PCSK9 expression), resulting in increased LDLR expression and LDL clearance; ER Ca2+ is identified as a master regulator of SREBP-2 activation upstream of its proteolytic processing.","method":"Hepatic cell treatment with caffeine/caffeine analogs, ER Ca2+ measurement, PCSK9/LDLR expression, human volunteer cohort, mechanistic Ca2+ manipulation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic Ca2+ link demonstrated in vitro and partially in vivo; replicated in human cohort","pmids":["35140212"],"is_preprint":false},{"year":2022,"finding":"NF-κB activation by pro-inflammatory cytokines in endothelial cells reduces accessible cholesterol, leading to heightened sterol sensing and downstream canonical SCAP-SREBP-2 cleavage/activation; NF-κB induces STARD10, which mediates accessible cholesterol homeostasis in ECs and links inflammation to SREBP-2 activation.","method":"Primary human endothelial cell treatment with cytokines, SREBP-2 cleavage assay, NF-κB inhibition, SCAP dependence assay, STARD10 identification by genetic screening","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic epistasis between NF-κB, STARD10, and canonical SCAP-SREBP-2 processing; single lab","pmids":["35959888"],"is_preprint":false},{"year":2022,"finding":"Unspliced XBP1 (XBP1-u) colocalizes with SREBP-2, inhibits SREBP-2 ubiquitination/proteasomal degradation, and stabilizes SREBP-2 protein to activate HMGCR transcription and cholesterol biosynthesis in hepatocellular carcinoma cells.","method":"Co-localization assay, ubiquitination assay, XBP1-u overexpression/knockdown, HMGCR expression measurement, cholesterol assay, xenograft","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-localization + ubiquitination assay + functional phenotype; single lab","pmids":["35933495"],"is_preprint":false},{"year":2023,"finding":"USP28, a deubiquitinating enzyme, directly binds mature SREBP-2 and deubiquitinates it, leading to SREBP-2 stabilization and increased mevalonate pathway enzyme expression; USP28 silencing reduces SREBP-2 protein levels and sensitizes squamous cancer cells to statins.","method":"Co-immunoprecipitation, deubiquitination assay, USP28 knockdown/knockout, metabolic flux analysis, tissue microarray, CRISPR/Cas9 SREBP-2 deletion in mouse cancer model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 — direct deubiquitination demonstrated + genetic validation in vivo; multiple orthogonal methods","pmids":["37202505"],"is_preprint":false},{"year":2020,"finding":"NBEAL1 interacts with SCAP and PAQR3 at the Golgi and regulates SREBP-2 processing and LDLR expression; loss of NBEAL1 in arteries (associated with coronary artery disease risk variants) downregulates LDLR by impairing this SCAP-SREBP-2 regulatory complex.","method":"Co-immunoprecipitation (NBEAL1-SCAP-PAQR3), NBEAL1 knockdown, SREBP-2 processing assay, LDLR expression measurement, human genetic association","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP identifies complex + functional KD phenotype; single lab","pmids":["32161285"],"is_preprint":false},{"year":2023,"finding":"PKCλ/ι (atypical PKC) phosphorylates SCAP, promoting its degradation and inhibiting SREBP-2 processing and activation; loss of PKCλ/ι upregulates SREBP-2 and cholesterol biosynthesis, driving aggressive serrated colorectal cancer tumorigenesis.","method":"PKCλ/ι conditional knockout in intestinal epithelial cells, SCAP phosphorylation and degradation assays, SREBP-2 processing measurement, tumor model in mice and human tissue analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — site-specific phosphorylation of SCAP by aPKC demonstrated + genetic KO + tumor model; multiple orthogonal methods","pmids":["38092754"],"is_preprint":false},{"year":2024,"finding":"Melanoma-derived lactate activates SREBP-2 in tumor-associated dendritic cells, driving their transformation into mature regulatory DCs (mregDCs) that suppress antitumor CD8+ T cell responses; DC-specific genetic silencing or pharmacologic inhibition of SREBP-2 restores antitumor immunity and suppresses melanoma progression.","method":"Transcriptional and metabolic profiling, DC-specific SREBP-2 genetic silencing, pharmacologic SREBP-2 inhibition, CD8+ T cell functional assays, preclinical melanoma models, human sentinel lymph node analysis","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic silencing + pharmacologic inhibition + multiple in vivo models + human tissue validation","pmids":["38728412"],"is_preprint":false},{"year":2022,"finding":"SREBP-2 directly binds the promoter region of NLRC4 in keratinocytes and transactivates it in response to LCN2/24p3R signaling, linking cholesterol biosynthetic signaling to NLRC4 inflammasome activation and psoriatic inflammation.","method":"ChIP demonstrating SREBP-2 binding to NLRC4 promoter, SREBP-2 siRNA knockdown in keratinocytes, imiquimod-induced mouse model with SREBP-2 suppression","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus in vivo knockdown with defined phenotype; single lab","pmids":["35120997"],"is_preprint":false},{"year":2021,"finding":"SREBP-2 directly binds promoter regions of mesenchymal genes (snai1, α-smooth muscle actin, vimentin, N-cadherin) and transactivates them in endothelial cells, inducing an endothelial-to-mesenchymal transition phenotype associated with pulmonary fibrosis; endothelial-specific SREBP-2 transgenic mice show exacerbated bleomycin-induced pulmonary fibrosis.","method":"Transcriptome analysis (SREBP-2 overexpression), ChIP (SREBP-2 binding to mesenchymal gene promoters), EC-SREBP2(N)-Tg mouse + bleomycin model, human IPF lung specimens","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus transgenic mouse model with functional phenotype; single lab","pmids":["34806652"],"is_preprint":false},{"year":2022,"finding":"HMGB1 regulates LDL transcytosis in endothelial cells through SREBP-2: loss of nuclear HMGB1 reduces SREBP-2 protein half-life and decreases SR-BI expression; conversely, LDL induces HMGB1 nuclear translocation in an SR-BI-dependent manner, creating a positive feedback loop. The effect requires SREBP-2 and SR-BI but not extracellular HMGB1 or RAGE.","method":"siRNA knockdown (HMGB1, SR-BI, SREBP-2), SREBP-2 protein stability assay, total internal reflection fluorescence microscopy of LDL transcytosis, HMGB1 nuclear localization imaging, endothelial HMGB1 KO mouse aortic LDL accumulation assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple siRNA epistasis experiments + protein stability + localization + in vivo mouse model; multiple orthogonal methods","pmids":["33054399"],"is_preprint":false},{"year":2022,"finding":"SREBP-2-activated transcription of lipid metabolism genes promotes Zika virus (ZIKV) infection of dendritic cells; ZIKV infection increases SREBP recruitment to lipid gene promoters, and pharmacologic inhibition or genetic silencing of SREBP-2 suppresses ZIKV infection.","method":"Genomics profiling of ZIKV-infected vs. uninfected DCs, ChIP (SREBP recruitment), pharmacologic/siRNA inhibition of SREBP-2, viral infection assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus pharmacologic/genetic epistasis; single lab","pmids":["36097162"],"is_preprint":false},{"year":2022,"finding":"KIF11 interacts with SREBP-2 protein and attenuates its ubiquitination-mediated degradation, stabilizing SREBP-2 and increasing mevalonate pathway enzyme expression to drive cholesterol synthesis and tumor progression in pancreatic ductal adenocarcinoma.","method":"Co-immunoprecipitation (KIF11-SREBP-2), ubiquitination assay, KIF11 overexpression/knockdown, SREBP-2-dependent rescue experiments, xenograft model","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + ubiquitination assay + functional epistasis; single lab","pmids":["35619540"],"is_preprint":false},{"year":2021,"finding":"SREBP-2 transactivates YAP target genes (including VCAM1, ICAM1, CYR61) in endothelial cells exposed to uric acid or monosodium urate; SREBP-2 knockdown by siRNA partially abolishes uric acid-induced YAP activity and pro-inflammatory gene expression, identifying SREBP2-YAP as a pathway driving gout-induced endothelial dysfunction.","method":"siRNA knockdown, adenovirus-SREBP2 overexpression, RNA sequencing, real-time PCR, endothelial transgenic mouse (SREBP2 OE), hyperuricemia mouse model, EndoPAT human assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA epistasis + genetic mouse models; single lab","pmids":["33977576"],"is_preprint":false},{"year":2023,"finding":"Disassociation of ERLIN2 from SCAP upon SNX10 deletion enhances SCAP-mediated SREBP-2 activation, increasing cholesterol biosynthesis and intestinal stem cell stemness, which promotes mucosal healing in colitis models.","method":"Conditional SNX10 KO in intestinal epithelial cells/ISCs, ERLIN2-SCAP co-immunoprecipitation, SREBP-2 activation assay, cholesterol measurement, organoid and mouse colitis models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifies ERLIN2-SCAP complex + conditional KO with defined phenotype; single lab","pmids":["37647408"],"is_preprint":false}],"current_model":"SREBP-2 (encoded by SREBF2) is an ER-anchored bHLH-Zip transcription factor that, when sterols are low, undergoes sequential sterol-regulated (site-1) and sterol-independent (site-2) proteolytic cleavages to release its N-terminal transcription factor domain, which enters the nucleus to directly bind SRE-1 elements and activate genes for cholesterol biosynthesis (HMGCR, HMGCS1, FDFT1), uptake (LDLR, NPC1L1), and broader lipid metabolism (ACSL1, IDH1, PCSK9, CASP7); its activity is post-translationally regulated by multiple mechanisms including ubiquitination by ITCH and deubiquitination by USP28, phosphorylation/dephosphorylation by PP2A, conformational activation of its chaperone SCAP by RNF5-mediated Lys-29 ubiquitination at K305, and repression via epigenetic silencing of the SREBF2 gene by the FoxO3-Sirt6 axis; the SREBF2 locus also encodes intronic miR-33a, which coordinately suppresses cholesterol export (via ABCA1) and fatty acid oxidation, and SREBP-2 functions as a transcriptional co-activator with Quaking (Qki) for cholesterol biosynthesis genes required for myelination and lens transparency, while also transactivating non-canonical targets including c-Myc, YAP, mesenchymal genes, and Transferrin in context-dependent settings."},"narrative":{"teleology":[{"year":1993,"claim":"The identity of SREBP-2 as a bHLH-Zip transcription factor that binds SRE-1 elements and activates cholesterol-related gene transcription was established, answering the fundamental question of what protein mediates sterol-responsive transcription.","evidence":"cDNA cloning with in vitro DNA-binding and cotransfection reporter assays in HEK293 cells","pmids":["7903453"],"confidence":"High","gaps":["Mechanism of ER-to-nucleus release unknown","In vivo target gene repertoire undefined","Relationship to SREBP-1 isoform unclear"]},{"year":1996,"claim":"The two-step proteolytic cleavage mechanism was resolved—a sterol-regulated first cleavage in the ER lumenal loop and a sterol-independent second cleavage within the transmembrane domain—explaining how SREBP-2 is liberated from the ER membrane to enter the nucleus.","evidence":"H-Ras–SREBP-2 fusion proteins, mutant CHO cell lines, cell fractionation, and transcriptional reporters","pmids":["8674110"],"confidence":"High","gaps":["Identity of site-1 and site-2 proteases not yet determined in this study","SCAP chaperone mechanism not yet linked"]},{"year":1997,"claim":"Genomic characterization of SREBF2 revealed a promoter SRE-1 element, establishing a feed-forward autoregulatory loop for SREBP-2 transcription in response to sterol depletion.","evidence":"Genomic cloning, sequencing, and 5'-flanking region analysis","pmids":["9070916"],"confidence":"High","gaps":["Quantitative contribution of autoregulation to SREBP-2 protein levels in vivo uncharacterized"]},{"year":2003,"claim":"SREBP-2's direct target repertoire was expanded beyond cholesterol/LDL genes to include IDH1, linking sterol-regulated transcription to NADPH supply for biosynthetic pathways.","evidence":"EMSA demonstrating direct SRE binding in the IDH1 promoter, mutagenesis, promoter-reporter assays","pmids":["12923220"],"confidence":"High","gaps":["Metabolic flux consequences of SREBP-2-driven NADPH generation not measured"]},{"year":2004,"claim":"A mechanism for cross-talk between ER stress and lipogenesis was revealed: ATF6 directly binds nuclear SREBP-2 and recruits HDAC1 to SRE-bound promoters, attenuating SREBP-2 transcriptional output.","evidence":"GST pull-down, co-immunoprecipitation, ChIP, and reporter assays in liver cells","pmids":["14765107"],"confidence":"High","gaps":["Whether ATF6-SREBP-2 interaction occurs in non-hepatic tissues unknown","Structural basis of leucine-zipper interaction unresolved"]},{"year":2009,"claim":"SREBP-2 was shown to directly bind the CASP7 promoter, extending its transcriptional reach to apoptotic machinery and raising the question of non-metabolic SREBP-2 functions.","evidence":"ChIP and siRNA knockdown with qPCR/Western blot readouts","pmids":["19323650"],"confidence":"Medium","gaps":["Functional consequence of SREBP-2-driven caspase-7 expression for apoptosis not fully tested","Single-lab finding"]},{"year":2010,"claim":"The discovery of intronic miR-33a within SREBF2 revealed a coordinated genetic program: while SREBP-2 protein activates cholesterol synthesis, the co-transcribed miRNA suppresses cholesterol efflux (ABCA1) and fatty acid oxidation, maximizing intracellular cholesterol retention.","evidence":"miRNA identification within SREBF2 intron 16, transfection-based translation inhibition, cholesterol export, and fatty acid oxidation functional assays","pmids":["20732877"],"confidence":"High","gaps":["Tissue-specific regulation of miR-33a processing relative to SREBP-2 mRNA not addressed","Therapeutic targeting of miR-33a vs. SREBP-2 not distinguished"]},{"year":2010,"claim":"NPC1L1 was established as a direct SREBP-2 transcriptional target, explaining how cholesterol absorption is coordinately upregulated with biosynthesis during sterol depletion.","evidence":"ChIP confirming in vivo SREBP-2 binding to NPC1L1 promoter, luciferase reporter, SREBP-2 overexpression rescue, human liver biopsy correlation","pmids":["20460578"],"confidence":"High","gaps":["Relative contribution of SREBP-2 vs. other factors to NPC1L1 regulation in intestine not quantified"]},{"year":2013,"claim":"An epigenetic brake on SREBP-2 was identified: FoxO3 recruits the deacetylase Sirt6 to the SREBF2 promoter, establishing repressive chromatin (deacetylated H3K9/H3K56) and reducing hepatic cholesterol biosynthesis—connecting nutrient sensing to SREBP-2 transcriptional silencing.","evidence":"Hepatic Sirt6 knockout mice, ChIP for H3 acetylation marks, in vivo overexpression rescue in obese mice","pmids":["23881913"],"confidence":"High","gaps":["Whether FoxO3-Sirt6 axis operates in extrahepatic tissues unknown","Kinetics of chromatin remodeling at the SREBF2 locus uncharacterized"]},{"year":2014,"claim":"A post-translational activation mechanism for nuclear SREBP-2 was uncovered: PP2A physically interacts with and dephosphorylates nuclear SREBP-2 upon cholesterol depletion, enhancing its DNA-binding capacity independently of proteolytic processing or nuclear import.","evidence":"Co-immunoprecipitation, ChIP, okadaic acid inhibition, PP2A siRNA, LDL uptake assays","pmids":["24770487"],"confidence":"High","gaps":["Specific phosphorylation sites on SREBP-2 regulated by PP2A not mapped","Kinase counteracting PP2A on SREBP-2 not identified"]},{"year":2014,"claim":"Hepatic insulin receptor signaling was shown to be required for SREBP-2 activation in response to feeding and statin treatment, placing insulin upstream of SREBP-2 processing in liver and explaining metabolic syndrome-associated cholesterol dysregulation.","evidence":"Liver insulin receptor knockout mice (LIRKO), microarray, statin and ezetimibe epistasis","pmids":["24516236"],"confidence":"High","gaps":["Molecular step at which insulin receptor signaling intersects SCAP-SREBP-2 not defined"]},{"year":2015,"claim":"Multiple layers of SREBP-2 regulation were defined in parallel: ITCH-mediated ubiquitination promotes SREBP-2 degradation; FXR transcriptionally induces SREBF2 yet simultaneously blocks processing via INSIG-2A; ERBB4–PI3K–mTORC1/2 signaling stimulates SREBP-2 cleavage; and SREBP-2 knockout is embryonic lethal while hypomorphic mice reveal SREBP-2 is required for hepatic SREBF1c expression.","evidence":"ApoE−/−ITCH−/− mice with ubiquitination assays; FXR ChIP-seq with Scap−/− epistasis; ERBB4 signaling with S1P inhibitor epistasis; SREBP-2 KO/hypomorph mouse models","pmids":["25777360","25593129","26535009","26685326"],"confidence":"High","gaps":["Specific ubiquitin chain types on SREBP-2 from ITCH not characterized","How FXR-induced miR-33a vs. INSIG-2A balance is achieved in different nutritional states unknown","Developmental cause of SREBP-2 null embryonic lethality unresolved"]},{"year":2015,"claim":"SREBP-2 was linked to non-canonical transcriptional targets in cancer: it directly binds and activates the c-Myc promoter, inducing cancer stem cell-like properties in prostate cancer.","evidence":"ChIP, promoter reporter, SREBP-2 overexpression/knockdown, xenograft model","pmids":["26883200"],"confidence":"Medium","gaps":["Whether c-Myc transactivation by SREBP-2 occurs in non-cancer contexts not tested","Single-lab finding"]},{"year":2016,"claim":"SREBP-2 directly activates ACSL1 transcription via a specific SRE, connecting cholesterol-sensing transcription to long-chain fatty acid activation and broadening SREBP-2's role in integrating lipid metabolism.","evidence":"EMSA with SRE mutagenesis, reporter assay, SREBP-2 siRNA in HepG2, statin treatment in hamsters and mice","pmids":["26728456"],"confidence":"High","gaps":["Functional metabolic flux consequences of ACSL1 regulation by SREBP-2 not quantified"]},{"year":2020,"claim":"The mechanism by which SCAP conformation is regulated was advanced: RNF5-mediated K29-linked polyubiquitination of SCAP at K305 enhances SCAP luminal loop 1–loop 7 interaction, a conformational change that activates SCAP-SREBP-2 transport and processing.","evidence":"RNF5 overexpression/knockdown, K305R SCAP mutant in SCAP-deficient cells, ubiquitination assays, co-immunoprecipitation","pmids":["32054686"],"confidence":"High","gaps":["Whether RNF5 activity on SCAP is sterol-regulated not determined","Structural details of how K29-ubiquitin chains alter SCAP conformation lacking"]},{"year":2020,"claim":"SREBP-2 was shown to directly transactivate Transferrin in circulating tumor cells, suppressing ferroptosis by reducing iron and lipid peroxidation—establishing a non-canonical anti-ferroptotic function.","evidence":"scRNA-seq of CTCs, SREBP-2/TF knockdown, ferroptosis induction, lipid peroxidation measurement, xenograft","pmids":["33203734"],"confidence":"Medium","gaps":["Direct SREBP-2 binding to TF promoter not shown by ChIP","Generalizability beyond melanoma CTCs untested"]},{"year":2021,"claim":"Quaking (Qki) was identified as a transcriptional co-activator of SREBP-2 that co-recruits SREBP-2 and RNA Pol II to cholesterol biosynthesis gene promoters in the lens and oligodendrocytes, explaining why Qki loss causes cataracts and hypomyelination despite normal SREBP-2 levels.","evidence":"Lens-specific and NSC/OPC-specific conditional Qki KO mice, ChIP for SREBP-2 and Pol II, cholesterol measurement, sterol rescue","pmids":["34021134","33942715"],"confidence":"High","gaps":["Whether Qki-SREBP-2 interaction is direct or mediated by additional factors not fully resolved","Tissue-specific co-activator requirements in other SREBP-2-dependent cell types unexplored"]},{"year":2021,"claim":"A 25-hydroxycholesterol–SREBP-2 axis was found to control germinal center B cell fate: 25-HC restrains SREBP-2 in GC B cells, and ectopic SREBP-2 drives rapid plasma cell differentiation, establishing SREBP-2 as a metabolic rheostat for humoral immunity.","evidence":"Ch25h−/− mice, B cell-specific SREBP-2 overexpression/deficiency, plasma cell assays, Salmonella infection model","pmids":["34644558"],"confidence":"High","gaps":["Downstream cholesterol-dependent effectors mediating plasma cell commitment not identified","Whether dietary cholesterol modulates this axis in humans unknown"]},{"year":2021,"claim":"SREBP-2 was shown to directly bind and transactivate mesenchymal gene promoters (snai1, αSMA, vimentin, N-cadherin) in endothelial cells, driving endothelial-to-mesenchymal transition relevant to pulmonary fibrosis.","evidence":"Transcriptome analysis, ChIP for SREBP-2 at mesenchymal gene promoters, EC-SREBP2(N) transgenic mice with bleomycin model, human IPF specimens","pmids":["34806652"],"confidence":"Medium","gaps":["Whether mesenchymal gene transactivation requires SRE elements or alternative motifs not defined","Single-lab finding"]},{"year":2022,"claim":"Multiple upstream regulators of SREBP-2 processing and stability were elaborated: ER Ca2+ was identified as a master brake on SREBP-2 activation; NF-κB–STARD10 signaling controls accessible cholesterol to trigger SCAP-SREBP-2 processing in endothelial cells; unspliced XBP1 stabilizes SREBP-2 by inhibiting its ubiquitination; KIF11 physically interacts with SREBP-2 to attenuate its degradation; and caspase-3 mediates an alternative SREBP-2 cleavage in HCC.","evidence":"ER Ca2+ manipulation with caffeine/analogs and human cohort; NF-κB inhibition and STARD10 genetic screen in ECs; XBP1-u co-localization and ubiquitination assays; KIF11 Co-IP and ubiquitination assay in PDAC; CASP3-SREBP-2 cleavage assay in drug-resistant HCC xenografts","pmids":["35140212","35959888","35933495","35619540","35767704"],"confidence":"Medium","gaps":["ER Ca2+ sensor linking calcium to SREBP-2 processing not identified","STARD10's cholesterol transfer mechanism and specificity not defined","XBP1-u stabilization mechanism lacks structural detail","KIF11-SREBP-2 interaction domain not mapped","CASP3 cleavage site on SREBP-2 not identified"]},{"year":2022,"claim":"SREBP-2's non-canonical transcriptional targets were further expanded to include NLRC4 in keratinocytes (linking cholesterol signaling to inflammasome activation in psoriasis), YAP effector genes in endothelial cells (linking uric acid to endothelial dysfunction), and Zika virus co-opted lipid genes in dendritic cells.","evidence":"ChIP for SREBP-2 at NLRC4 promoter plus imiquimod mouse model; SREBP-2 siRNA epistasis on YAP activity in ECs plus hyperuricemia mouse; ChIP and SREBP-2 inhibition in ZIKV-infected DCs","pmids":["35120997","33977576","36097162"],"confidence":"Medium","gaps":["Generalizability of NLRC4 regulation beyond keratinocytes untested","Mechanism by which SREBP-2 activates YAP target genes (direct binding vs. indirect) incompletely resolved","Host-virus specificity of SREBP-2 exploitation unknown"]},{"year":2023,"claim":"SREBP-2 protein was shown to be stabilized by deubiquitination: USP28 directly binds mature SREBP-2 and removes ubiquitin chains, increasing mevalonate pathway output—and USP28 loss sensitizes squamous cancer cells to statins, establishing a druggable vulnerability.","evidence":"Co-immunoprecipitation, in vitro deubiquitination assay, USP28 KO, CRISPR SREBP-2 deletion in mouse cancer model, metabolic flux","pmids":["37202505"],"confidence":"High","gaps":["Ubiquitin chain type removed by USP28 not specified","Whether USP28 counteracts ITCH specifically on SREBP-2 not tested"]},{"year":2023,"claim":"PKCλ/ι was identified as a negative regulator of SREBP-2 by phosphorylating SCAP to promote its degradation; loss of PKCλ/ι unleashes SREBP-2-driven cholesterol biosynthesis that drives serrated colorectal cancer, connecting atypical PKC signaling to tumor-promoting SREBP-2 activation.","evidence":"Intestinal epithelial PKCλ/ι conditional KO, SCAP phosphorylation/degradation assays, SREBP-2 processing, mouse tumor model, human tissue","pmids":["38092754"],"confidence":"High","gaps":["Specific SCAP phosphorylation sites targeted by PKCλ/ι not fully mapped","Whether other aPKC isoforms compensate not addressed"]},{"year":2024,"claim":"SREBP-2 was shown to act as a metabolic reprogramming switch in tumor-associated dendritic cells: melanoma-derived lactate activates SREBP-2, transforming DCs into immunosuppressive mregDCs that dampen CD8+ T cell responses, and DC-specific SREBP-2 silencing restores antitumor immunity.","evidence":"Transcriptional/metabolic profiling, DC-specific genetic silencing, pharmacologic SREBP-2 inhibition, CD8+ T cell assays, preclinical melanoma models, human sentinel lymph node analysis","pmids":["38728412"],"confidence":"High","gaps":["Specific SREBP-2 target genes mediating mregDC transformation not defined","Whether other tumor-derived metabolites converge on SREBP-2 in DCs unknown"]},{"year":null,"claim":"Key unresolved questions include the identity of the kinase(s) opposing PP2A on nuclear SREBP-2, the structural basis for how diverse post-translational modifications (ubiquitination, phosphorylation, deubiquitination) coordinately tune SREBP-2 stability and DNA binding, and whether the expanding non-canonical target repertoire reflects bona fide SRE-dependent transcription or context-specific chromatin remodeling.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of SREBP-2 N-terminal domain bound to SRE-1 exists","Systematic mapping of SREBP-2 phosphorylation sites and their functional significance is lacking","Genome-wide ChIP-seq defining the complete SREBP-2 cistrome across tissues has not been integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,7,8,10,33,34]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,4,5,7,8,10,21,23,24,33,34]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,14,23]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,4,5,8,10,15,19,20,23,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,6,7,21,33,34]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,14,18,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[22,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,16,31]}],"complexes":["SCAP-SREBP-2 ER transport complex","ATF6-SREBP-2-HDAC1 repressive complex","Qki-SREBP-2 co-activator complex"],"partners":["SCAP","ATF6","PP2A","ITCH","USP28","QKI","KIF11","HDAC1"],"other_free_text":[]},"mechanistic_narrative":"SREBF2 encodes SREBP-2, a master transcriptional regulator of cholesterol homeostasis that functions as an ER-anchored bHLH-Zip transcription factor; upon sterol depletion, it undergoes sequential proteolytic cleavages—a sterol-regulated site-1 cleavage in the ER lumenal loop and a sterol-independent site-2 cleavage within the first transmembrane domain—to release an N-terminal fragment that translocates to the nucleus and binds SRE-1 elements to activate cholesterol biosynthesis (HMGCR, HMGCS1), uptake (LDLR, NPC1L1), and auxiliary metabolic genes (IDH1, ACSL1, PCSK9) [PMID:7903453, PMID:8674110, PMID:20460578, PMID:26728456]. SREBP-2 processing is controlled by multiple upstream inputs including SCAP conformation (regulated by RNF5-mediated K29-linked ubiquitination at SCAP K305 and PKCλ/ι-mediated SCAP phosphorylation/degradation), ER calcium levels, insulin receptor signaling, and NF-κB–STARD10-dependent accessible cholesterol sensing [PMID:32054686, PMID:38092754, PMID:35140212, PMID:24516236, PMID:35959888]; nuclear SREBP-2 activity is further modulated by PP2A-dependent dephosphorylation that promotes DNA binding, ITCH-mediated ubiquitination driving degradation, USP28-mediated deubiquitination conferring stabilization, ATF6-HDAC1 complex recruitment that represses transcription, and epigenetic silencing of the SREBF2 locus by the FoxO3–Sirt6 axis [PMID:24770487, PMID:25777360, PMID:37202505, PMID:14765107, PMID:23881913]. Beyond canonical lipid metabolism, SREBP-2 co-activates cholesterol biosynthesis genes with Quaking (Qki) to support myelination and lens transparency, its intronic miR-33a coordinately suppresses cholesterol efflux via ABCA1, and in context-dependent settings it transactivates non-canonical targets including c-Myc, Transferrin, mesenchymal genes, NLRC4, and YAP effectors, linking it to cancer stemness, ferroptosis resistance, endothelial-to-mesenchymal transition, inflammasome activation, and immunomodulation in dendritic cells [PMID:34021134, PMID:33942715, PMID:20732877, PMID:26883200, PMID:33203734, PMID:34806652, PMID:35120997, PMID:38728412]."},"prefetch_data":{"uniprot":{"accession":"Q12772","full_name":"Sterol regulatory element-binding protein 2","aliases":["Class D basic helix-loop-helix protein 2","bHLHd2","Sterol regulatory element-binding transcription factor 2"],"length_aa":1141,"mass_kda":123.7,"function":"Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 2), which is embedded in the endoplasmic reticulum membrane (PubMed:32322062). Low sterol concentrations promote processing of this form, releasing the transcription factor form that translocates into the nucleus and activates transcription of genes involved in cholesterol biosynthesis (PubMed:32322062) Key transcription factor that regulates expression of genes involved in cholesterol biosynthesis (PubMed:12177166, PubMed:32322062). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:12177166, PubMed:7903453). Regulates transcription of genes related to cholesterol synthesis pathway (PubMed:12177166, PubMed:32322062)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q12772/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SREBF2","classification":"Not Classified","n_dependent_lines":72,"n_total_lines":1208,"dependency_fraction":0.059602649006622516},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SREBF2","total_profiled":1310},"omim":[{"mim_id":"621173","title":"G PROTEIN-COUPLED RECEPTOR 146; GPR146","url":"https://www.omim.org/entry/621173"},{"mim_id":"620640","title":"RING FINGER PROTEIN 145; RNF145","url":"https://www.omim.org/entry/620640"},{"mim_id":"613486","title":"MICRO RNA 33B; MIR33B","url":"https://www.omim.org/entry/613486"},{"mim_id":"612912","title":"TRANSMEMBRANE PROTEIN 97; TMEM97","url":"https://www.omim.org/entry/612912"},{"mim_id":"612156","title":"MICRO RNA 33A; MIR33A","url":"https://www.omim.org/entry/612156"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SREBF2"},"hgnc":{"alias_symbol":["SREBP2","bHLHd2"],"prev_symbol":[]},"alphafold":{"accession":"Q12772","domains":[{"cath_id":"4.10.280.10","chopping":"338-399","consensus_level":"medium","plddt":86.3252,"start":338,"end":399},{"cath_id":"-","chopping":"756-818_831-852_863-912","consensus_level":"medium","plddt":75.9667,"start":756,"end":912},{"cath_id":"1.20.1310","chopping":"943-1045","consensus_level":"medium","plddt":83.3946,"start":943,"end":1045},{"cath_id":"1.25.40","chopping":"1054-1059_1074-1141","consensus_level":"medium","plddt":76.8405,"start":1054,"end":1141}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12772","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12772-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12772-F1-predicted_aligned_error_v6.png","plddt_mean":61.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SREBF2","jax_strain_url":"https://www.jax.org/strain/search?query=SREBF2"},"sequence":{"accession":"Q12772","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12772.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12772/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12772"}},"corpus_meta":[{"pmid":"7903453","id":"PMC_7903453","title":"SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7903453","citation_count":544,"is_preprint":false},{"pmid":"8674110","id":"PMC_8674110","title":"Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment.","date":"1996","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8674110","citation_count":462,"is_preprint":false},{"pmid":"20732877","id":"PMC_20732877","title":"Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20732877","citation_count":303,"is_preprint":false},{"pmid":"19231010","id":"PMC_19231010","title":"Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH.","date":"2009","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/19231010","citation_count":291,"is_preprint":false},{"pmid":"33203734","id":"PMC_33203734","title":"The Lipogenic Regulator SREBP2 Induces Transferrin in Circulating Melanoma Cells and Suppresses Ferroptosis.","date":"2020","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/33203734","citation_count":195,"is_preprint":false},{"pmid":"14765107","id":"PMC_14765107","title":"ATF6 modulates SREBP2-mediated lipogenesis.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/14765107","citation_count":182,"is_preprint":false},{"pmid":"27001618","id":"PMC_27001618","title":"Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer's disease neuropathological deficits.","date":"2016","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27001618","citation_count":171,"is_preprint":false},{"pmid":"23881913","id":"PMC_23881913","title":"Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6.","date":"2013","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/23881913","citation_count":148,"is_preprint":false},{"pmid":"17916878","id":"PMC_17916878","title":"ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2.","date":"2007","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/17916878","citation_count":131,"is_preprint":false},{"pmid":"27211556","id":"PMC_27211556","title":"Irisin Inhibits Hepatic Cholesterol Synthesis via AMPK-SREBP2 Signaling.","date":"2016","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/27211556","citation_count":113,"is_preprint":false},{"pmid":"32883951","id":"PMC_32883951","title":"COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm.","date":"2020","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32883951","citation_count":110,"is_preprint":false},{"pmid":"26883200","id":"PMC_26883200","title":"SREBP-2 promotes stem cell-like properties and metastasis by transcriptional activation of c-Myc in prostate cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26883200","citation_count":93,"is_preprint":false},{"pmid":"35767704","id":"PMC_35767704","title":"Caspase-3-Induced Activation of SREBP2 Drives Drug Resistance via Promotion of Cholesterol Biosynthesis in Hepatocellular Carcinoma.","date":"2022","source":"Cancer 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gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells.","date":"2003","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/12923220","citation_count":77,"is_preprint":false},{"pmid":"36534812","id":"PMC_36534812","title":"Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36534812","citation_count":73,"is_preprint":false},{"pmid":"21356514","id":"PMC_21356514","title":"Regulation of lipid homeostasis by the bifunctional SREBF2-miR33a locus.","date":"2011","source":"Cell 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it contains an acidic NH2-terminal transactivation domain, a conserved bHLH-Zip motif, and a long COOH-terminal regulatory domain. In vitro DNA binding and in vivo reporter assays demonstrated SRE-1 binding specificity and transcriptional activation capacity.\",\n      \"method\": \"cDNA cloning, in vitro DNA binding assay, cotransfection reporter assay in HEK293 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original reconstitution of DNA-binding and transactivation with multiple orthogonal methods; foundational paper with 544 citations\",\n      \"pmids\": [\"7903453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SREBP-2 is released from the endoplasmic reticulum membrane by two sequential proteolytic cleavages: the first, sterol-regulated, occurs in the lumenal loop between the two transmembrane segments; the second, sterol-independent, occurs within the first transmembrane domain. The liberated NH2-terminal transcription factor domain then enters the nucleus to activate cholesterol biosynthesis and uptake genes.\",\n      \"method\": \"H-Ras-SREBP-2 fusion protein expression, mutant CHO cell analysis, cell fractionation, transcriptional reporter assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with defined mutants and fusion proteins; mechanistic cleavage pathway established; 462 citations\",\n      \"pmids\": [\"8674110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The SREBF2 gene spans 72 kb and is composed of 19 exons and 18 introns; a perfect 10-bp SRE-1 sequence is present in the SREBF2 promoter, providing a mechanism for autoregulation of its own transcription by sterol levels.\",\n      \"method\": \"Genomic cloning, sequencing, 5'-flanking region analysis, transcription start site mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural determination of gene, replicated SRE-1 identification\",\n      \"pmids\": [\"9070916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ATF6 N-terminal fragment (ATF6(N)) directly binds to SREBP-2 N-terminal fragment (SREBP2(N)) through its leucine-zipper domain; the ATF6-SREBP-2 complex recruits HDAC1 to SRE-bound SREBP-2, attenuating SREBP-2 transcriptional activity and suppressing lipogenesis in liver cells.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, deletion mutagenesis, chromatin immunoprecipitation (ChIP), reporter assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (GST pull-down, Co-IP, ChIP, reporter assay) in single study\",\n      \"pmids\": [\"14765107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SREBP-2 directly activates transcription of the IDH1 (cytosolic NADP-dependent isocitrate dehydrogenase) gene by binding to a specific SRE sequence (GTGGGCTGAG) in the IDH1 promoter, linking cholesterol/fatty acid biosynthetic regulation to NADPH generation.\",\n      \"method\": \"Promoter-reporter assays, electrophoretic mobility shift assay (EMSA), mutagenesis, sterol-depletion experiments\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct DNA binding demonstrated by EMSA and mutagenesis with functional reporter validation\",\n      \"pmids\": [\"12923220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The primary transcript of SREBF2 contains an intronic miRNA (miR-33a) that reduces cellular cholesterol export by inhibiting translation of ABCA1, and also inhibits fatty acid β-oxidation by suppressing CPT1A, HADHB, and CROT, functionally coupling cholesterol synthesis promotion with prevention of cholesterol export and lipid degradation.\",\n      \"method\": \"Identification of miRNA within SREBF2 intron, transfection-based translation inhibition assays, functional cholesterol export and FAO assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery with multiple functional readouts; replicated widely (303 citations)\",\n      \"pmids\": [\"20732877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FoxO3 recruits Sirt6 to the Srebp2 gene promoter, where Sirt6 deacetylates histone H3 at lysines 9 and 56 to promote a repressive chromatin state, thereby reducing hepatic SREBP-2 expression and cholesterol biosynthesis. Hepatic Sirt6 deficiency elevates cholesterol levels, and Sirt6 or FoxO3 overexpression improves hypercholesterolemia in obese mice.\",\n      \"method\": \"Hepatic Sirt6 knockout mice, chromatin immunoprecipitation, overexpression in vivo, cholesterol measurement\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + ChIP + in vivo rescue; multiple orthogonal methods\",\n      \"pmids\": [\"23881913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SREBP-2 directly binds to an SREBP-2-binding element in the 5'-flanking c-Myc promoter region and drives c-Myc transcriptional activation, inducing cancer stem cell-like properties and metastasis in prostate cancer cells.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter reporter assay, SREBP-2 overexpression/knockdown with functional assays (proliferation, invasion, prostasphere, xenograft)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter plus functional phenotype, single lab\",\n      \"pmids\": [\"26883200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SREBP-2 directly induces transcription of the long-chain acyl-CoA synthetase 1 (ACSL1) C-transcript via a specific SRE motif in the ACSL1 C-promoter; knockdown of endogenous SREBP-2 in HepG2 cells reduces ACSL1 expression, linking cholesterol-sensing SREBP-2 to fatty acid activation.\",\n      \"method\": \"Promoter activity assay, DNA binding assay (EMSA), SREBP-2 knockdown, statin treatment in hamsters and mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — promoter assay + EMSA mutagenesis + siRNA knockdown; multiple orthogonal methods in one study\",\n      \"pmids\": [\"26728456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SREBP-1 and SREBP-2 directly bind the proximal promoter region of the CASP7 gene (encoding caspase 7) as demonstrated by chromatin immunoprecipitation, and knockdown of SREBP-1/2 strongly reduces caspase 7 mRNA and protein expression, identifying CASP7 as a direct SREBP target.\",\n      \"method\": \"ChIP, siRNA knockdown, quantitative PCR, Western blot\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus siRNA knockdown with defined phenotype, single lab\",\n      \"pmids\": [\"19323650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SREBP-2 directly regulates NPC1L1 promoter activity in a dose-dependent manner and binds to the NPC1L1 promoter in vivo; overexpression of active SREBP-2 protects NPC1L1 from inhibitory effects, establishing NPC1L1 as a direct SREBP-2 target gene in human liver.\",\n      \"method\": \"Luciferase promoter assay, ChIP, SREBP-2 overexpression, correlation analysis in human liver biopsies\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP confirms in vivo binding, reporter and overexpression rescue; multiple methods\",\n      \"pmids\": [\"20460578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Curcumin reduces SREBP-2 DNA-binding activity and nuclear translocation partly through AMPK activation, thereby suppressing NPC1L1 promoter activity and cholesterol absorption; overexpression of active SREBP-2 rescues NPC1L1 from curcumin inhibition, demonstrating SREBP-2 mediates NPC1L1 regulation.\",\n      \"method\": \"Reporter assay, Western blot, AMPK activation measurement, SREBP-2 overexpression rescue, EMSA\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter + rescue + EMSA; single lab\",\n      \"pmids\": [\"21527728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Oligomeric Aβ42 inhibits SREBP-2 proteolytic cleavage in neurons, causing decreased protein prenylation and cholesterol sequestration; supplying geranylgeranyl pyrophosphate to Aβ-treated neurons restores prenylation, reduces cholesterol sequestration, and prevents neurotoxicity, identifying SREBP-2 as a target of Aβ neurotoxicity.\",\n      \"method\": \"Intracellular Aβ42 delivery, SREBP-2 cleavage assay (Western blot), prenylation assays, isoprenoid supplementation rescue, cortex analysis in TgCRND8 mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic rescue experiments and in vivo validation; single lab\",\n      \"pmids\": [\"22573671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLR4-MyD88-NF-κB signaling increases SCAP expression and promotes abnormal SCAP translocation from the ER to the Golgi, activating the SCAP-SREBP-2 pathway to upregulate LDLR and HMG-CoAR expression and drive macrophage foam cell formation; MyD88 knockdown or IKK inhibition blocks these effects.\",\n      \"method\": \"siRNA knockdown, Western blot, RT-PCR, immunofluorescence/confocal microscopy, cholesterol measurement in THP-1 macrophages\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA epistasis plus organelle localization imaging; single lab\",\n      \"pmids\": [\"23335792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PP2A directly interacts with nuclear SREBP-2 in response to cholesterol depletion, alters its phosphorylation state, and promotes SREBP-2 DNA binding to the LDLR SRE promoter element, increasing LDLR expression and LDL uptake; PP2A inhibition or depletion by okadaic acid/siRNA abolishes SREBP-2 binding without affecting cleavage or nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, okadaic acid inhibition, ChIP/DNA binding assay, LDL uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct physical interaction (Co-IP) + functional epistasis (siRNA) + DNA binding assay; multiple orthogonal methods\",\n      \"pmids\": [\"24770487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Hepatic insulin receptor is required for normal SREBP-2 activation in response to feeding and statin treatment; LIRKO mice lacking liver insulin receptors show suppressed SREBP-2 and cholesterologenic gene expression, and the response of SREBP-2 to both fasting/refeeding and statin treatment is abolished, while ezetimibe (cholesterol absorption inhibitor) can still induce SREBP-2 in LIRKO livers.\",\n      \"method\": \"Liver insulin receptor knockout mice (LIRKO), gene expression microarray, Western blot, statin/ezetimibe treatment\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple pharmacological epistasis experiments; well-controlled in vivo study\",\n      \"pmids\": [\"24516236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERBB4 activation by neuregulin-1 induces SREBP-2 cleavage and the appearance of mature SREBP-2 through a PI3K- and mTORC1/2-dependent (but AKT- and mTORC1-independent) pathway, increasing expression of cholesterol biosynthesis and LDL uptake genes; pharmacological inhibition of S1P protease blocks NRG1-induced cholesterol gene expression.\",\n      \"method\": \"ERBB4-ICD expression, NRG1 ligand stimulation, PI3K/mTOR inhibitor treatment, S1P protease inhibitor, immunoblot of cleaved SREBP-2, gene expression assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic dissection of pathway; single lab\",\n      \"pmids\": [\"26535009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FXR activation in mice induces SREBP-2 gene transcription (via an FXR response element in intron 10 of Srebp-2) and increases miR-33 levels, but simultaneously induces INSIG-2A, which prevents SCAP-mediated SREBP-2 processing, thereby uncoupling miR-33 and SREBP-2 target gene programs.\",\n      \"method\": \"ChIP-seq (FXR response element identification), FXR agonist treatment in mice, Scap-/- epistasis, Western blot for precursor and nuclear SREBP-2, miR-33 quantification\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq + genetic epistasis in Scap-/- + multiple in vivo pharmacological experiments\",\n      \"pmids\": [\"25593129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ITCH E3 ubiquitin ligase ubiquitinates SREBP-2, promoting its clearance; loss of ITCH reduces SREBP-2 ubiquitination and degradation, increasing nuclear SREBP-2 and LDLR expression, lowering circulating cholesterol. ITCH also ubiquitinates SIRT6 to promote its breakdown, reducing fatty acid oxidation.\",\n      \"method\": \"ApoE-/-ITCH-/- mouse model, bone marrow transplantation, ubiquitination assay, cholesterol measurement, gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mouse model with ubiquitination mechanistic follow-up; single lab\",\n      \"pmids\": [\"25777360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SREBP-2 deficiency causes embryonic lethality in mice, with surviving null mice showing alopecia, attenuated growth, and reduced adipose tissue; hypomorphic mice with low SREBP-2 have reduced hepatic cholesterol and nearly abolished liver SREBF1c transcripts, demonstrating SREBP-2 is required for SREBF1c expression in liver and for embryonic development.\",\n      \"method\": \"SREBP-2 knockout and hypomorphic mouse generation, gene expression analysis, cholesterol measurement, histology\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO/hypomorph models with tissue-specific phenotype characterization\",\n      \"pmids\": [\"26685326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ring finger protein 5 (RNF5), an ER-anchored E3 ubiquitin ligase, mediates Lys-29-linked polyubiquitination of SCAP at Lys-305 in cytosolic loop 2, enhancing the interaction between SCAP luminal loops 1 and 7 (a conformational change required for SCAP-SREBP-2 activation) and thereby activating SREBP-2 and cholesterol biosynthesis.\",\n      \"method\": \"siRNA knockdown, RNF5 overexpression, ubiquitination assay, K305R SCAP mutant in SCAP-deficient cells, co-immunoprecipitation, SREBP-2 target gene measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-specific mutagenesis + ubiquitination assay + conformational mechanistic insight; multiple orthogonal methods\",\n      \"pmids\": [\"32054686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SREBP2 directly induces transcription of the iron carrier Transferrin (TF) gene in circulating melanoma cells, reducing intracellular iron pools, reactive oxygen species, and lipid peroxidation, thereby suppressing ferroptosis and conferring drug resistance.\",\n      \"method\": \"Single-cell RNA-seq, knockdown of SREBP2/TF, ferroptosis induction assays, lipid peroxidation measurement, xenograft tumor formation\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional induction with functional KD rescue; single lab, CTC model\",\n      \"pmids\": [\"33203734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"25-hydroxycholesterol (25-HC) produced by follicular dendritic cells directly restrains SREBP-2 activation in germinal center B cells; ectopic SREBP-2 expression drives rapid plasma cell differentiation, while SREBP-2 deficiency reduces plasma cell output, establishing a 25-HC-SREBP2 axis that shapes intestinal IgA responses.\",\n      \"method\": \"Ch25h-/- mouse model, B cell-specific SREBP-2 overexpression/deficiency, plasma cell differentiation assays, immunization and Salmonella infection models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models (KO, overexpression, cell-type specific) with defined functional readouts\",\n      \"pmids\": [\"34644558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Quaking (Qki) functions as a transcriptional co-activator of SREBP-2 in eye lens and oligodendrocytes by recruiting SREBP-2 and RNA polymerase II to promoter regions of cholesterol biosynthesis genes; Qki-deficient lens-specific mice show reduced cholesterol and progressive cataracts rescued by topical sterol administration.\",\n      \"method\": \"Lens-specific Qki knockout mice, transcriptome analysis, ChIP (SREBP-2 and Pol II), cholesterol measurement, sterol rescue experiment, direct DNA-binding assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP demonstrates co-recruitment of Qki and SREBP-2 to gene promoters; genetic KO with in vivo rescue\",\n      \"pmids\": [\"34021134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Qki-5 acts as a transcriptional co-activator of SREBP-2 in oligodendrocytes to control cholesterol biosynthesis gene transcription required for myelinogenesis; Qki depletion in neural stem cells or OPCs impairs cholesterol biosynthesis and myelin assembly without blocking oligodendrocyte differentiation.\",\n      \"method\": \"Conditional Qki knockout in neural stem cells and OPCs, cholesterol measurement, transcriptome analysis, myelination phenotype assessment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined cellular and molecular phenotype, corroborating lens study (PMID 34021134)\",\n      \"pmids\": [\"33942715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Caspase-3 (CASP3) mediates cleavage of SREBP-2 from the ER to promote cholesterol biosynthesis, which drives cancer stem cell expansion and resistance to sorafenib/lenvatinib via activation of the sonic hedgehog signaling pathway in hepatocellular carcinoma.\",\n      \"method\": \"Drug-resistant patient-derived xenografts, RNA-seq, CASP3 cleavage of SREBP-2 (Western blot), SREBP-2 loss-of-function, simvastatin treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic CASP3-cleavage identified + pathway epistasis; single lab\",\n      \"pmids\": [\"35767704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Caffeine increases hepatic ER Ca2+ levels, which blocks SREBP-2 transcriptional activation (and thus PCSK9 expression), resulting in increased LDLR expression and LDL clearance; ER Ca2+ is identified as a master regulator of SREBP-2 activation upstream of its proteolytic processing.\",\n      \"method\": \"Hepatic cell treatment with caffeine/caffeine analogs, ER Ca2+ measurement, PCSK9/LDLR expression, human volunteer cohort, mechanistic Ca2+ manipulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic Ca2+ link demonstrated in vitro and partially in vivo; replicated in human cohort\",\n      \"pmids\": [\"35140212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NF-κB activation by pro-inflammatory cytokines in endothelial cells reduces accessible cholesterol, leading to heightened sterol sensing and downstream canonical SCAP-SREBP-2 cleavage/activation; NF-κB induces STARD10, which mediates accessible cholesterol homeostasis in ECs and links inflammation to SREBP-2 activation.\",\n      \"method\": \"Primary human endothelial cell treatment with cytokines, SREBP-2 cleavage assay, NF-κB inhibition, SCAP dependence assay, STARD10 identification by genetic screening\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic epistasis between NF-κB, STARD10, and canonical SCAP-SREBP-2 processing; single lab\",\n      \"pmids\": [\"35959888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Unspliced XBP1 (XBP1-u) colocalizes with SREBP-2, inhibits SREBP-2 ubiquitination/proteasomal degradation, and stabilizes SREBP-2 protein to activate HMGCR transcription and cholesterol biosynthesis in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-localization assay, ubiquitination assay, XBP1-u overexpression/knockdown, HMGCR expression measurement, cholesterol assay, xenograft\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-localization + ubiquitination assay + functional phenotype; single lab\",\n      \"pmids\": [\"35933495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP28, a deubiquitinating enzyme, directly binds mature SREBP-2 and deubiquitinates it, leading to SREBP-2 stabilization and increased mevalonate pathway enzyme expression; USP28 silencing reduces SREBP-2 protein levels and sensitizes squamous cancer cells to statins.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, USP28 knockdown/knockout, metabolic flux analysis, tissue microarray, CRISPR/Cas9 SREBP-2 deletion in mouse cancer model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct deubiquitination demonstrated + genetic validation in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"37202505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NBEAL1 interacts with SCAP and PAQR3 at the Golgi and regulates SREBP-2 processing and LDLR expression; loss of NBEAL1 in arteries (associated with coronary artery disease risk variants) downregulates LDLR by impairing this SCAP-SREBP-2 regulatory complex.\",\n      \"method\": \"Co-immunoprecipitation (NBEAL1-SCAP-PAQR3), NBEAL1 knockdown, SREBP-2 processing assay, LDLR expression measurement, human genetic association\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP identifies complex + functional KD phenotype; single lab\",\n      \"pmids\": [\"32161285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PKCλ/ι (atypical PKC) phosphorylates SCAP, promoting its degradation and inhibiting SREBP-2 processing and activation; loss of PKCλ/ι upregulates SREBP-2 and cholesterol biosynthesis, driving aggressive serrated colorectal cancer tumorigenesis.\",\n      \"method\": \"PKCλ/ι conditional knockout in intestinal epithelial cells, SCAP phosphorylation and degradation assays, SREBP-2 processing measurement, tumor model in mice and human tissue analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-specific phosphorylation of SCAP by aPKC demonstrated + genetic KO + tumor model; multiple orthogonal methods\",\n      \"pmids\": [\"38092754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Melanoma-derived lactate activates SREBP-2 in tumor-associated dendritic cells, driving their transformation into mature regulatory DCs (mregDCs) that suppress antitumor CD8+ T cell responses; DC-specific genetic silencing or pharmacologic inhibition of SREBP-2 restores antitumor immunity and suppresses melanoma progression.\",\n      \"method\": \"Transcriptional and metabolic profiling, DC-specific SREBP-2 genetic silencing, pharmacologic SREBP-2 inhibition, CD8+ T cell functional assays, preclinical melanoma models, human sentinel lymph node analysis\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic silencing + pharmacologic inhibition + multiple in vivo models + human tissue validation\",\n      \"pmids\": [\"38728412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SREBP-2 directly binds the promoter region of NLRC4 in keratinocytes and transactivates it in response to LCN2/24p3R signaling, linking cholesterol biosynthetic signaling to NLRC4 inflammasome activation and psoriatic inflammation.\",\n      \"method\": \"ChIP demonstrating SREBP-2 binding to NLRC4 promoter, SREBP-2 siRNA knockdown in keratinocytes, imiquimod-induced mouse model with SREBP-2 suppression\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus in vivo knockdown with defined phenotype; single lab\",\n      \"pmids\": [\"35120997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBP-2 directly binds promoter regions of mesenchymal genes (snai1, α-smooth muscle actin, vimentin, N-cadherin) and transactivates them in endothelial cells, inducing an endothelial-to-mesenchymal transition phenotype associated with pulmonary fibrosis; endothelial-specific SREBP-2 transgenic mice show exacerbated bleomycin-induced pulmonary fibrosis.\",\n      \"method\": \"Transcriptome analysis (SREBP-2 overexpression), ChIP (SREBP-2 binding to mesenchymal gene promoters), EC-SREBP2(N)-Tg mouse + bleomycin model, human IPF lung specimens\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus transgenic mouse model with functional phenotype; single lab\",\n      \"pmids\": [\"34806652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMGB1 regulates LDL transcytosis in endothelial cells through SREBP-2: loss of nuclear HMGB1 reduces SREBP-2 protein half-life and decreases SR-BI expression; conversely, LDL induces HMGB1 nuclear translocation in an SR-BI-dependent manner, creating a positive feedback loop. The effect requires SREBP-2 and SR-BI but not extracellular HMGB1 or RAGE.\",\n      \"method\": \"siRNA knockdown (HMGB1, SR-BI, SREBP-2), SREBP-2 protein stability assay, total internal reflection fluorescence microscopy of LDL transcytosis, HMGB1 nuclear localization imaging, endothelial HMGB1 KO mouse aortic LDL accumulation assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple siRNA epistasis experiments + protein stability + localization + in vivo mouse model; multiple orthogonal methods\",\n      \"pmids\": [\"33054399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SREBP-2-activated transcription of lipid metabolism genes promotes Zika virus (ZIKV) infection of dendritic cells; ZIKV infection increases SREBP recruitment to lipid gene promoters, and pharmacologic inhibition or genetic silencing of SREBP-2 suppresses ZIKV infection.\",\n      \"method\": \"Genomics profiling of ZIKV-infected vs. uninfected DCs, ChIP (SREBP recruitment), pharmacologic/siRNA inhibition of SREBP-2, viral infection assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus pharmacologic/genetic epistasis; single lab\",\n      \"pmids\": [\"36097162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF11 interacts with SREBP-2 protein and attenuates its ubiquitination-mediated degradation, stabilizing SREBP-2 and increasing mevalonate pathway enzyme expression to drive cholesterol synthesis and tumor progression in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation (KIF11-SREBP-2), ubiquitination assay, KIF11 overexpression/knockdown, SREBP-2-dependent rescue experiments, xenograft model\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + ubiquitination assay + functional epistasis; single lab\",\n      \"pmids\": [\"35619540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBP-2 transactivates YAP target genes (including VCAM1, ICAM1, CYR61) in endothelial cells exposed to uric acid or monosodium urate; SREBP-2 knockdown by siRNA partially abolishes uric acid-induced YAP activity and pro-inflammatory gene expression, identifying SREBP2-YAP as a pathway driving gout-induced endothelial dysfunction.\",\n      \"method\": \"siRNA knockdown, adenovirus-SREBP2 overexpression, RNA sequencing, real-time PCR, endothelial transgenic mouse (SREBP2 OE), hyperuricemia mouse model, EndoPAT human assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA epistasis + genetic mouse models; single lab\",\n      \"pmids\": [\"33977576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Disassociation of ERLIN2 from SCAP upon SNX10 deletion enhances SCAP-mediated SREBP-2 activation, increasing cholesterol biosynthesis and intestinal stem cell stemness, which promotes mucosal healing in colitis models.\",\n      \"method\": \"Conditional SNX10 KO in intestinal epithelial cells/ISCs, ERLIN2-SCAP co-immunoprecipitation, SREBP-2 activation assay, cholesterol measurement, organoid and mouse colitis models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifies ERLIN2-SCAP complex + conditional KO with defined phenotype; single lab\",\n      \"pmids\": [\"37647408\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SREBP-2 (encoded by SREBF2) is an ER-anchored bHLH-Zip transcription factor that, when sterols are low, undergoes sequential sterol-regulated (site-1) and sterol-independent (site-2) proteolytic cleavages to release its N-terminal transcription factor domain, which enters the nucleus to directly bind SRE-1 elements and activate genes for cholesterol biosynthesis (HMGCR, HMGCS1, FDFT1), uptake (LDLR, NPC1L1), and broader lipid metabolism (ACSL1, IDH1, PCSK9, CASP7); its activity is post-translationally regulated by multiple mechanisms including ubiquitination by ITCH and deubiquitination by USP28, phosphorylation/dephosphorylation by PP2A, conformational activation of its chaperone SCAP by RNF5-mediated Lys-29 ubiquitination at K305, and repression via epigenetic silencing of the SREBF2 gene by the FoxO3-Sirt6 axis; the SREBF2 locus also encodes intronic miR-33a, which coordinately suppresses cholesterol export (via ABCA1) and fatty acid oxidation, and SREBP-2 functions as a transcriptional co-activator with Quaking (Qki) for cholesterol biosynthesis genes required for myelination and lens transparency, while also transactivating non-canonical targets including c-Myc, YAP, mesenchymal genes, and Transferrin in context-dependent settings.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SREBF2 encodes SREBP-2, a master transcriptional regulator of cholesterol homeostasis that functions as an ER-anchored bHLH-Zip transcription factor; upon sterol depletion, it undergoes sequential proteolytic cleavages—a sterol-regulated site-1 cleavage in the ER lumenal loop and a sterol-independent site-2 cleavage within the first transmembrane domain—to release an N-terminal fragment that translocates to the nucleus and binds SRE-1 elements to activate cholesterol biosynthesis (HMGCR, HMGCS1), uptake (LDLR, NPC1L1), and auxiliary metabolic genes (IDH1, ACSL1, PCSK9) [PMID:7903453, PMID:8674110, PMID:20460578, PMID:26728456]. SREBP-2 processing is controlled by multiple upstream inputs including SCAP conformation (regulated by RNF5-mediated K29-linked ubiquitination at SCAP K305 and PKCλ/ι-mediated SCAP phosphorylation/degradation), ER calcium levels, insulin receptor signaling, and NF-κB–STARD10-dependent accessible cholesterol sensing [PMID:32054686, PMID:38092754, PMID:35140212, PMID:24516236, PMID:35959888]; nuclear SREBP-2 activity is further modulated by PP2A-dependent dephosphorylation that promotes DNA binding, ITCH-mediated ubiquitination driving degradation, USP28-mediated deubiquitination conferring stabilization, ATF6-HDAC1 complex recruitment that represses transcription, and epigenetic silencing of the SREBF2 locus by the FoxO3–Sirt6 axis [PMID:24770487, PMID:25777360, PMID:37202505, PMID:14765107, PMID:23881913]. Beyond canonical lipid metabolism, SREBP-2 co-activates cholesterol biosynthesis genes with Quaking (Qki) to support myelination and lens transparency, its intronic miR-33a coordinately suppresses cholesterol efflux via ABCA1, and in context-dependent settings it transactivates non-canonical targets including c-Myc, Transferrin, mesenchymal genes, NLRC4, and YAP effectors, linking it to cancer stemness, ferroptosis resistance, endothelial-to-mesenchymal transition, inflammasome activation, and immunomodulation in dendritic cells [PMID:34021134, PMID:33942715, PMID:20732877, PMID:26883200, PMID:33203734, PMID:34806652, PMID:35120997, PMID:38728412].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"The identity of SREBP-2 as a bHLH-Zip transcription factor that binds SRE-1 elements and activates cholesterol-related gene transcription was established, answering the fundamental question of what protein mediates sterol-responsive transcription.\",\n      \"evidence\": \"cDNA cloning with in vitro DNA-binding and cotransfection reporter assays in HEK293 cells\",\n      \"pmids\": [\"7903453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ER-to-nucleus release unknown\", \"In vivo target gene repertoire undefined\", \"Relationship to SREBP-1 isoform unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The two-step proteolytic cleavage mechanism was resolved—a sterol-regulated first cleavage in the ER lumenal loop and a sterol-independent second cleavage within the transmembrane domain—explaining how SREBP-2 is liberated from the ER membrane to enter the nucleus.\",\n      \"evidence\": \"H-Ras–SREBP-2 fusion proteins, mutant CHO cell lines, cell fractionation, and transcriptional reporters\",\n      \"pmids\": [\"8674110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of site-1 and site-2 proteases not yet determined in this study\", \"SCAP chaperone mechanism not yet linked\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Genomic characterization of SREBF2 revealed a promoter SRE-1 element, establishing a feed-forward autoregulatory loop for SREBP-2 transcription in response to sterol depletion.\",\n      \"evidence\": \"Genomic cloning, sequencing, and 5'-flanking region analysis\",\n      \"pmids\": [\"9070916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of autoregulation to SREBP-2 protein levels in vivo uncharacterized\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"SREBP-2's direct target repertoire was expanded beyond cholesterol/LDL genes to include IDH1, linking sterol-regulated transcription to NADPH supply for biosynthetic pathways.\",\n      \"evidence\": \"EMSA demonstrating direct SRE binding in the IDH1 promoter, mutagenesis, promoter-reporter assays\",\n      \"pmids\": [\"12923220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Metabolic flux consequences of SREBP-2-driven NADPH generation not measured\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A mechanism for cross-talk between ER stress and lipogenesis was revealed: ATF6 directly binds nuclear SREBP-2 and recruits HDAC1 to SRE-bound promoters, attenuating SREBP-2 transcriptional output.\",\n      \"evidence\": \"GST pull-down, co-immunoprecipitation, ChIP, and reporter assays in liver cells\",\n      \"pmids\": [\"14765107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATF6-SREBP-2 interaction occurs in non-hepatic tissues unknown\", \"Structural basis of leucine-zipper interaction unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"SREBP-2 was shown to directly bind the CASP7 promoter, extending its transcriptional reach to apoptotic machinery and raising the question of non-metabolic SREBP-2 functions.\",\n      \"evidence\": \"ChIP and siRNA knockdown with qPCR/Western blot readouts\",\n      \"pmids\": [\"19323650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SREBP-2-driven caspase-7 expression for apoptosis not fully tested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The discovery of intronic miR-33a within SREBF2 revealed a coordinated genetic program: while SREBP-2 protein activates cholesterol synthesis, the co-transcribed miRNA suppresses cholesterol efflux (ABCA1) and fatty acid oxidation, maximizing intracellular cholesterol retention.\",\n      \"evidence\": \"miRNA identification within SREBF2 intron 16, transfection-based translation inhibition, cholesterol export, and fatty acid oxidation functional assays\",\n      \"pmids\": [\"20732877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific regulation of miR-33a processing relative to SREBP-2 mRNA not addressed\", \"Therapeutic targeting of miR-33a vs. SREBP-2 not distinguished\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"NPC1L1 was established as a direct SREBP-2 transcriptional target, explaining how cholesterol absorption is coordinately upregulated with biosynthesis during sterol depletion.\",\n      \"evidence\": \"ChIP confirming in vivo SREBP-2 binding to NPC1L1 promoter, luciferase reporter, SREBP-2 overexpression rescue, human liver biopsy correlation\",\n      \"pmids\": [\"20460578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of SREBP-2 vs. other factors to NPC1L1 regulation in intestine not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"An epigenetic brake on SREBP-2 was identified: FoxO3 recruits the deacetylase Sirt6 to the SREBF2 promoter, establishing repressive chromatin (deacetylated H3K9/H3K56) and reducing hepatic cholesterol biosynthesis—connecting nutrient sensing to SREBP-2 transcriptional silencing.\",\n      \"evidence\": \"Hepatic Sirt6 knockout mice, ChIP for H3 acetylation marks, in vivo overexpression rescue in obese mice\",\n      \"pmids\": [\"23881913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FoxO3-Sirt6 axis operates in extrahepatic tissues unknown\", \"Kinetics of chromatin remodeling at the SREBF2 locus uncharacterized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A post-translational activation mechanism for nuclear SREBP-2 was uncovered: PP2A physically interacts with and dephosphorylates nuclear SREBP-2 upon cholesterol depletion, enhancing its DNA-binding capacity independently of proteolytic processing or nuclear import.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, okadaic acid inhibition, PP2A siRNA, LDL uptake assays\",\n      \"pmids\": [\"24770487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation sites on SREBP-2 regulated by PP2A not mapped\", \"Kinase counteracting PP2A on SREBP-2 not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Hepatic insulin receptor signaling was shown to be required for SREBP-2 activation in response to feeding and statin treatment, placing insulin upstream of SREBP-2 processing in liver and explaining metabolic syndrome-associated cholesterol dysregulation.\",\n      \"evidence\": \"Liver insulin receptor knockout mice (LIRKO), microarray, statin and ezetimibe epistasis\",\n      \"pmids\": [\"24516236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular step at which insulin receptor signaling intersects SCAP-SREBP-2 not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Multiple layers of SREBP-2 regulation were defined in parallel: ITCH-mediated ubiquitination promotes SREBP-2 degradation; FXR transcriptionally induces SREBF2 yet simultaneously blocks processing via INSIG-2A; ERBB4–PI3K–mTORC1/2 signaling stimulates SREBP-2 cleavage; and SREBP-2 knockout is embryonic lethal while hypomorphic mice reveal SREBP-2 is required for hepatic SREBF1c expression.\",\n      \"evidence\": \"ApoE−/−ITCH−/− mice with ubiquitination assays; FXR ChIP-seq with Scap−/− epistasis; ERBB4 signaling with S1P inhibitor epistasis; SREBP-2 KO/hypomorph mouse models\",\n      \"pmids\": [\"25777360\", \"25593129\", \"26535009\", \"26685326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitin chain types on SREBP-2 from ITCH not characterized\", \"How FXR-induced miR-33a vs. INSIG-2A balance is achieved in different nutritional states unknown\", \"Developmental cause of SREBP-2 null embryonic lethality unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"SREBP-2 was linked to non-canonical transcriptional targets in cancer: it directly binds and activates the c-Myc promoter, inducing cancer stem cell-like properties in prostate cancer.\",\n      \"evidence\": \"ChIP, promoter reporter, SREBP-2 overexpression/knockdown, xenograft model\",\n      \"pmids\": [\"26883200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether c-Myc transactivation by SREBP-2 occurs in non-cancer contexts not tested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"SREBP-2 directly activates ACSL1 transcription via a specific SRE, connecting cholesterol-sensing transcription to long-chain fatty acid activation and broadening SREBP-2's role in integrating lipid metabolism.\",\n      \"evidence\": \"EMSA with SRE mutagenesis, reporter assay, SREBP-2 siRNA in HepG2, statin treatment in hamsters and mice\",\n      \"pmids\": [\"26728456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional metabolic flux consequences of ACSL1 regulation by SREBP-2 not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The mechanism by which SCAP conformation is regulated was advanced: RNF5-mediated K29-linked polyubiquitination of SCAP at K305 enhances SCAP luminal loop 1–loop 7 interaction, a conformational change that activates SCAP-SREBP-2 transport and processing.\",\n      \"evidence\": \"RNF5 overexpression/knockdown, K305R SCAP mutant in SCAP-deficient cells, ubiquitination assays, co-immunoprecipitation\",\n      \"pmids\": [\"32054686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RNF5 activity on SCAP is sterol-regulated not determined\", \"Structural details of how K29-ubiquitin chains alter SCAP conformation lacking\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"SREBP-2 was shown to directly transactivate Transferrin in circulating tumor cells, suppressing ferroptosis by reducing iron and lipid peroxidation—establishing a non-canonical anti-ferroptotic function.\",\n      \"evidence\": \"scRNA-seq of CTCs, SREBP-2/TF knockdown, ferroptosis induction, lipid peroxidation measurement, xenograft\",\n      \"pmids\": [\"33203734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SREBP-2 binding to TF promoter not shown by ChIP\", \"Generalizability beyond melanoma CTCs untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Quaking (Qki) was identified as a transcriptional co-activator of SREBP-2 that co-recruits SREBP-2 and RNA Pol II to cholesterol biosynthesis gene promoters in the lens and oligodendrocytes, explaining why Qki loss causes cataracts and hypomyelination despite normal SREBP-2 levels.\",\n      \"evidence\": \"Lens-specific and NSC/OPC-specific conditional Qki KO mice, ChIP for SREBP-2 and Pol II, cholesterol measurement, sterol rescue\",\n      \"pmids\": [\"34021134\", \"33942715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Qki-SREBP-2 interaction is direct or mediated by additional factors not fully resolved\", \"Tissue-specific co-activator requirements in other SREBP-2-dependent cell types unexplored\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A 25-hydroxycholesterol–SREBP-2 axis was found to control germinal center B cell fate: 25-HC restrains SREBP-2 in GC B cells, and ectopic SREBP-2 drives rapid plasma cell differentiation, establishing SREBP-2 as a metabolic rheostat for humoral immunity.\",\n      \"evidence\": \"Ch25h−/− mice, B cell-specific SREBP-2 overexpression/deficiency, plasma cell assays, Salmonella infection model\",\n      \"pmids\": [\"34644558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream cholesterol-dependent effectors mediating plasma cell commitment not identified\", \"Whether dietary cholesterol modulates this axis in humans unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"SREBP-2 was shown to directly bind and transactivate mesenchymal gene promoters (snai1, αSMA, vimentin, N-cadherin) in endothelial cells, driving endothelial-to-mesenchymal transition relevant to pulmonary fibrosis.\",\n      \"evidence\": \"Transcriptome analysis, ChIP for SREBP-2 at mesenchymal gene promoters, EC-SREBP2(N) transgenic mice with bleomycin model, human IPF specimens\",\n      \"pmids\": [\"34806652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mesenchymal gene transactivation requires SRE elements or alternative motifs not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple upstream regulators of SREBP-2 processing and stability were elaborated: ER Ca2+ was identified as a master brake on SREBP-2 activation; NF-κB–STARD10 signaling controls accessible cholesterol to trigger SCAP-SREBP-2 processing in endothelial cells; unspliced XBP1 stabilizes SREBP-2 by inhibiting its ubiquitination; KIF11 physically interacts with SREBP-2 to attenuate its degradation; and caspase-3 mediates an alternative SREBP-2 cleavage in HCC.\",\n      \"evidence\": \"ER Ca2+ manipulation with caffeine/analogs and human cohort; NF-κB inhibition and STARD10 genetic screen in ECs; XBP1-u co-localization and ubiquitination assays; KIF11 Co-IP and ubiquitination assay in PDAC; CASP3-SREBP-2 cleavage assay in drug-resistant HCC xenografts\",\n      \"pmids\": [\"35140212\", \"35959888\", \"35933495\", \"35619540\", \"35767704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ER Ca2+ sensor linking calcium to SREBP-2 processing not identified\", \"STARD10's cholesterol transfer mechanism and specificity not defined\", \"XBP1-u stabilization mechanism lacks structural detail\", \"KIF11-SREBP-2 interaction domain not mapped\", \"CASP3 cleavage site on SREBP-2 not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SREBP-2's non-canonical transcriptional targets were further expanded to include NLRC4 in keratinocytes (linking cholesterol signaling to inflammasome activation in psoriasis), YAP effector genes in endothelial cells (linking uric acid to endothelial dysfunction), and Zika virus co-opted lipid genes in dendritic cells.\",\n      \"evidence\": \"ChIP for SREBP-2 at NLRC4 promoter plus imiquimod mouse model; SREBP-2 siRNA epistasis on YAP activity in ECs plus hyperuricemia mouse; ChIP and SREBP-2 inhibition in ZIKV-infected DCs\",\n      \"pmids\": [\"35120997\", \"33977576\", \"36097162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability of NLRC4 regulation beyond keratinocytes untested\", \"Mechanism by which SREBP-2 activates YAP target genes (direct binding vs. indirect) incompletely resolved\", \"Host-virus specificity of SREBP-2 exploitation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"SREBP-2 protein was shown to be stabilized by deubiquitination: USP28 directly binds mature SREBP-2 and removes ubiquitin chains, increasing mevalonate pathway output—and USP28 loss sensitizes squamous cancer cells to statins, establishing a druggable vulnerability.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro deubiquitination assay, USP28 KO, CRISPR SREBP-2 deletion in mouse cancer model, metabolic flux\",\n      \"pmids\": [\"37202505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain type removed by USP28 not specified\", \"Whether USP28 counteracts ITCH specifically on SREBP-2 not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PKCλ/ι was identified as a negative regulator of SREBP-2 by phosphorylating SCAP to promote its degradation; loss of PKCλ/ι unleashes SREBP-2-driven cholesterol biosynthesis that drives serrated colorectal cancer, connecting atypical PKC signaling to tumor-promoting SREBP-2 activation.\",\n      \"evidence\": \"Intestinal epithelial PKCλ/ι conditional KO, SCAP phosphorylation/degradation assays, SREBP-2 processing, mouse tumor model, human tissue\",\n      \"pmids\": [\"38092754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific SCAP phosphorylation sites targeted by PKCλ/ι not fully mapped\", \"Whether other aPKC isoforms compensate not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SREBP-2 was shown to act as a metabolic reprogramming switch in tumor-associated dendritic cells: melanoma-derived lactate activates SREBP-2, transforming DCs into immunosuppressive mregDCs that dampen CD8+ T cell responses, and DC-specific SREBP-2 silencing restores antitumor immunity.\",\n      \"evidence\": \"Transcriptional/metabolic profiling, DC-specific genetic silencing, pharmacologic SREBP-2 inhibition, CD8+ T cell assays, preclinical melanoma models, human sentinel lymph node analysis\",\n      \"pmids\": [\"38728412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific SREBP-2 target genes mediating mregDC transformation not defined\", \"Whether other tumor-derived metabolites converge on SREBP-2 in DCs unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the kinase(s) opposing PP2A on nuclear SREBP-2, the structural basis for how diverse post-translational modifications (ubiquitination, phosphorylation, deubiquitination) coordinately tune SREBP-2 stability and DNA binding, and whether the expanding non-canonical target repertoire reflects bona fide SRE-dependent transcription or context-specific chromatin remodeling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of SREBP-2 N-terminal domain bound to SRE-1 exists\", \"Systematic mapping of SREBP-2 phosphorylation sites and their functional significance is lacking\", \"Genome-wide ChIP-seq defining the complete SREBP-2 cistrome across tissues has not been integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 7, 8, 10, 33, 34]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 4, 5, 7, 8, 10, 21, 23, 24, 33, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 14, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 4, 5, 8, 10, 15, 19, 20, 23, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 6, 7, 21, 33, 34]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 14, 18, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 16, 31]}\n    ],\n    \"complexes\": [\n      \"SCAP-SREBP-2 ER transport complex\",\n      \"ATF6-SREBP-2-HDAC1 repressive complex\",\n      \"Qki-SREBP-2 co-activator complex\"\n    ],\n    \"partners\": [\n      \"SCAP\",\n      \"ATF6\",\n      \"PP2A\",\n      \"ITCH\",\n      \"USP28\",\n      \"QKI\",\n      \"KIF11\",\n      \"HDAC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}