{"gene":"CREB3L3","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2001,"finding":"CREB-H (CREBH) is a liver-specific bZIP transcription factor localized to the ER via a transmembrane domain; deletion of the transmembrane domain causes nuclear translocation and increases transcriptional activity. Full-length GFP-CREBH localizes to perinuclear reticular structures, while the TM-deleted mutant localizes to the nucleus. CREBH binds CRE and box-B elements but not C/EBP, AP-1, or NF-κB elements.","method":"GFP fusion live imaging, gel mobility shift assay, GAL4 fusion transactivation assay, luciferase reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, EMSA, reporter assay, deletion mutagenesis) in a single rigorous study establishing localization and DNA-binding specificity","pmids":["11353085"],"is_preprint":false},{"year":2005,"finding":"CREB-H is activated by proteolytic cleavage that removes the C-terminal transmembrane domain, releasing a nuclear fragment. The active form binds to CRE, box-B, and ATF6-binding elements and activates the PEPCK-C promoter; this activation is further stimulated by cAMP and protein kinase A.","method":"Luciferase reporter assay, co-immunoprecipitation, promoter activation assay, cell proliferation assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in a single study; replication of cleavage/nuclear translocation mechanism consistent with other papers","pmids":["15800215"],"is_preprint":false},{"year":2006,"finding":"Upon ER stress, CREBH is cleaved by site-1 protease (S1P) and site-2 protease (S2P) at the Golgi to liberate an N-terminal fragment that translocates to the nucleus and activates transcription of acute phase response genes SAP and CRP. Proinflammatory cytokines (and LPS) induce CREBH expression and trigger its cleavage in vivo.","method":"In vivo cleavage assay, siRNA knockdown, promoter-luciferase reporter, mouse LPS/cytokine challenge","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic cleavage by defined proteases confirmed in vitro and in vivo with loss-of-function, replicated across multiple subsequent studies","pmids":["16469704"],"is_preprint":false},{"year":2007,"finding":"CREB-H is subject to N-linked glycosylation and undergoes ERAD: it is retrotranslocated from the ER to the cytosol, deglycosylated, and degraded by the proteasome under basal conditions. Proteasome inhibition diverts CREB-H from ERAD into the cleavage/nuclear-transport pathway. A cytoplasmic determinant (ERM) mediates ER retention; deletion of this motif causes constitutive Golgi localization and cleavage.","method":"Subcellular fractionation, proteasome inhibitor treatment, glycosylation analysis, deletion mutagenesis, nuclear transport assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and cell biological methods; competition between ERAD and RIP pathways mechanistically established","pmids":["17875199"],"is_preprint":false},{"year":2009,"finding":"PPARα directly binds to a PPRE in the CREBH promoter to induce CREBH expression in response to fatty acids and fasting. CREBH mRNA and nuclear protein are induced by fasting and suppressed by refeeding; this suppression is impaired in ob/ob mice.","method":"Luciferase reporter assay, EMSA, ChIP assay, promoter deletion analysis, PPARα agonist/antagonist treatment","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — EMSA and ChIP identify direct PPARα binding to CREBH promoter; supported by pharmacological gain/loss-of-function","pmids":["20006574"],"is_preprint":false},{"year":2010,"finding":"Unlike ATF6, whose ER retention is mediated by lumenal BiP binding, CREB-H ER retention is controlled by a membrane-proximal cytoplasmic determinant (ERM) conserved in the CREB3 family but absent in ATF6. The lumenal tail of CREB-H neither binds BiP nor is required for ER retention or Golgi transport; ERM deletion causes constitutive Golgi localization and cleavage by S1P.","method":"Domain deletion and swap mutagenesis, co-IP for BiP binding, fluorescence microscopy, constitutive cleavage assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-style domain-swap experiment with mutagenesis clearly dissects distinct ER-retention mechanism vs ATF6","pmids":["19883396"],"is_preprint":false},{"year":2010,"finding":"N-linked glycosylation of CREB-H at three luminal sites is required for its efficient proteolytic activation. Unglycosylated CREB-H mutant (all three N-glycosylation sites abolished) is retained in an inactive ER form and fails to be cleaved or activate transcription in response to S1P stimulation.","method":"Site-directed mutagenesis of glycosylation sites, brefeldin A / KDEL-S1P stimulation, transcription reporter assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple glycosylation site mutants characterized with functional transcription readouts; consistent with parallel ERAD study","pmids":["20356926"],"is_preprint":false},{"year":2010,"finding":"CREBH regulates hepatic gluconeogenesis: it is induced by fasting or insulin-resistant state in a dexamethasone- and PGC-1α-dependent manner; the active nuclear form (CREBH-N) binds an enhancer in the PEPCK-C and G6Pase promoters distinct from the classical CREB/CRTC2 sites; hepatic CREBH knockdown reduces blood glucose in mice.","method":"Adenoviral overexpression, siRNA knockdown, ChIP assay, promoter-luciferase, glucose tolerance/blood glucose measurement in mice","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ChIP showing CREBH binding to gluconeogenic promoters combined with in vivo knockdown phenotype; replicated by subsequent studies","pmids":["20374965"],"is_preprint":false},{"year":2011,"finding":"CB1R activation by 2-AG induces CREBH gene expression via JNK phosphorylation and c-Jun binding to an AP-1 site in the CREBH promoter. CREBH mediates CB1R-stimulated hepatic gluconeogenic gene expression and glucose production; endogenous CREBH knockdown abolishes 2-AG-induced gluconeogenesis.","method":"ChIP assay, promoter mutagenesis-luciferase, siRNA knockdown, glucose production assay in primary hepatocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP and promoter mutagenesis identify AP-1 site; loss-of-function abolishes phenotype in primary human and rat hepatocytes","pmids":["21693703"],"is_preprint":false},{"year":2011,"finding":"SMILE (small heterodimer partner-interacting leucine zipper protein) interacts with CREBH via its bZIP domain and represses CREBH-mediated transactivation. SMILE competes with PGC-1α coactivation of CREBH; curcumin induces SMILE through LKB1/AMPK signaling to selectively inhibit CREBH (not ATF6) target gene transcription.","method":"Co-IP, GST pulldown, ChIP, Gal4 fusion transactivation, siRNA knockdown, dominant-negative assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP establishes direct protein–protein interaction; ChIP confirms competition on endogenous promoter; loss-of-function controls","pmids":["21994947"],"is_preprint":false},{"year":2012,"finding":"CB1R agonist 2-AG induces Lipin1 gene expression in a CREBH-dependent manner; CREBH directly recruits to the Lipin1 promoter. This increases hepatic diacylglycerol levels and PKCε phosphorylation, thereby inhibiting insulin receptor signaling.","method":"ChIP assay, adenoviral CREBH overexpression/knockdown, DAG measurement, PKCε phosphorylation assay, insulin receptor signaling assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP shows CREBH binding to Lipin1 promoter; downstream PKCε/insulin signaling pathway defined by loss-of-function; single lab","pmids":["22989885"],"is_preprint":false},{"year":2013,"finding":"CREB-H contains a unique ATB domain (absent in all other human bZIP factors) essential for transcriptional activity. CREB-H activates secretory pathway genes (SPGs) and stimulates secretion of specific cargo including apolipoproteins (ApoA-IV, ApoAI) in liver cells.","method":"Drosophila ATB domain complementation, deletion mutagenesis, transcriptomics, ELISA for secreted proteins","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain swap in heterologous system plus endogenous target gene and secretion readouts; single lab, multiple methods","pmids":["23279168"],"is_preprint":false},{"year":2014,"finding":"CREBH and PPARα interact to form a functional binary transcriptional complex that binds integrated CRE–PPRE composite elements in the FGF21 promoter; PPARα requires CREBH to exert its trans-activation effect on FGF21. CREBH and PPARα mutually regulate each other's expression.","method":"Co-IP, ChIP, luciferase reporter, gain- and loss-of-function in mice (adenoviral and genetic), FGF21 protein measurement","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus ChIP demonstrating complex at endogenous FGF21 promoter; replicated in multiple subsequent studies","pmids":["24424044"],"is_preprint":false},{"year":2014,"finding":"CREBH directly activates Apoa4 (apolipoprotein A-IV) transcription via two tandem CREBH-binding sites (5'-CCACGTTG-3') in the promoter conserved between human and mouse; CREBH protein is constitutively processed to its active form in normal liver, with further increase during steatosis.","method":"ChIP, EMSA, luciferase reporter, CREBH-deficient mouse transcriptomics","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP and EMSA confirm direct binding; conserved binding site validated by mutagenesis; single lab","pmids":["24598141"],"is_preprint":false},{"year":2015,"finding":"CREBH is acetylated at lysine 294 (K294) within its bZIP domain during fasting. PCAF mediates acetylation, SIRT1 mediates deacetylation. K294 acetylation is required for CREBH–PPARα interaction and synergistic transcriptional activation of lipid metabolic target genes; acetylation-deficient (K294R) mutant abolishes this interaction and causes hepatic steatosis in vivo.","method":"Site-directed mutagenesis, co-IP, luciferase reporter, adenoviral K294 mutant injection into mice, hepatic lipid measurement","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis plus Co-IP plus in vivo phenotype; replicated in circadian study (PMID 28461393)","pmids":["26438600"],"is_preprint":false},{"year":2015,"finding":"CREBH directly activates the Fsp27β (liver-specific isoform) promoter (not the Fsp27α/PPARγ-driven promoter). Fsp27β localizes to lipid droplets and suppresses lipolysis; CREBH-driven Fsp27β expression promotes lipid droplet enlargement and triglyceride accumulation in the liver.","method":"Promoter-luciferase assay, adenoviral overexpression/KO mouse, Oil-Red-O staining, lipid droplet imaging","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter and in vivo KO/OE establish CREBH-specific regulation of Fsp27β; single lab","pmids":["25125366"],"is_preprint":false},{"year":2015,"finding":"The active nuclear form of CREB-H (CREB-H-ΔTC) is degraded by the SCF(β-TrCP) E3 ubiquitin ligase via K48-linked polyubiquitination. β-TrCP binds a conserved phosphodegron motif SDSGIS in CREB-H-ΔTC; phosphorylation of this motif is required for β-TrCP recognition and subsequent proteasomal degradation.","method":"Co-IP, ubiquitination assay, site-directed mutagenesis, siRNA knockdown of β-TrCP, cycloheximide chase","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution of ubiquitination, mutagenesis of phosphodegron, multiple orthogonal stability assays; single lab","pmids":["27029215"],"is_preprint":false},{"year":2015,"finding":"Phosphorylation of CREB-H within a serine-rich P-motif (around S87/S90) by CKII and GSK-3β targets CREB-H to the SCF(Fbw1a/β-TrCP) E3 ligase for proteasomal degradation. CREB-H directly interacts with Fbw1a in a phosphorylation-dependent manner; GSK-3 phosphorylation at adjacent serines primes subsequent CKII phosphorylation at S87/S90.","method":"In vitro kinase assay with CKII and GSK-3β, phosphospecific antibody, dominant-negative Cul1, Co-IP, site-directed mutagenesis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus mutagenesis plus dominant-negative E3 ligase; replicated by β-TrCP paper (PMID 27029215)","pmids":["26108621"],"is_preprint":false},{"year":2016,"finding":"CREBH proteolytic activation exhibits circadian rhythmicity controlled by the core clock oscillator BMAL1 and AKT/GSK3β signaling. GSK3β-mediated phosphorylation of CREBH modulates its association with COPII vesicle components to control ER-to-Golgi transport and subsequent proteolytic cleavage in a circadian manner.","method":"Circadian profiling of CREBH cleavage in mouse livers, BMAL1 KO, GSK3β inhibitor, COPII co-IP, phosphorylation assay","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (BMAL1 KO) and pharmacological (GSK3β inhibitor) combined with biochemical COPII interaction assay; multiple orthogonal methods","pmids":["27507854"],"is_preprint":false},{"year":2016,"finding":"Hepatic CREB3L3 independently controls fatty acid oxidation and ketogenesis in addition to its role in activating PPARα in an auto-loop; double knockout (Creb3l3-/-/Ppara-/-) mice show further suppression of oxidation/ketogenesis genes beyond either single KO, indicating independent contributions.","method":"Creb3l3-/- and Ppara-/- single and double knockout mouse phenotyping on ketogenic diet and fasting; gene expression analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double-KO, replicated across fasting and ketogenic diet conditions","pmids":["27982131"],"is_preprint":false},{"year":2016,"finding":"CREBH directly activates Apoa1 (apoA-I) gene transcription, contributing to HDL cholesterol production. CREBH deficiency in Ldlr-/- mice decreases HDL and apoA-I and accelerates atherosclerosis.","method":"Luciferase reporter assay, CREBH-deficient/Ldlr-/- double KO mouse phenotyping, lipid profiling","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus genetic loss-of-function with defined lipoprotein phenotype; single lab","pmids":["27417587"],"is_preprint":false},{"year":2016,"finding":"Intestinal CREBH directly regulates Npc1l1 (cholesterol transporter) promoter activity to suppress intestinal cholesterol absorption; CREBH transgenic (intestine) mice show reduced Npc1l1 expression and decreased plasma/hepatic cholesterol, while CREBH null mice show the opposite.","method":"Promoter-luciferase assay, CREBH intestine-specific transgenic and global KO mice, cholesterol absorption measurement, fecal cholesterol output","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter reporter plus reciprocal genetic models (transgenic and KO) with defined mechanistic target gene","pmids":["27818935"],"is_preprint":false},{"year":2017,"finding":"CREBH maintains circadian glucose homeostasis by regulating glycogenolysis (via PYGL) and gluconeogenesis (via PCK1 and G6PC). CREBH interacts with PPARα, and K294 acetylation controls this interaction and synergistic gluconeogenic activity across the circadian cycle.","method":"CREBH KO mouse circadian phenotyping, Co-IP, adenoviral K294 acetylation-site mutants, glycogen measurement, blood glucose profiling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype plus Co-IP plus mutagenesis across multiple metabolic readouts; extends prior acetylation finding (PMID 26438600)","pmids":["28461393"],"is_preprint":false},{"year":2017,"finding":"TLR/MyD88-dependent signaling activates CREBH in liver upon LPS. TRAF6 (E3 ubiquitin ligase, TLR mediator) interacts with CREBH in a MyD88-dependent manner and mediates K63-linked ubiquitination of CREBH to facilitate its cleavage and activation. Active CREBH then directly activates ApoA4 expression to modulate HDL.","method":"Co-IP (CREBH–TRAF6, CREBH–MyD88), K63-ubiquitination assay, ChIP on ApoA4 promoter, TLR/MyD88 KO mice, HDL measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and ubiquitination assay with linkage-specific antibody; genetic KO models confirming pathway; ChIP validates direct target","pmids":["27637329"],"is_preprint":false},{"year":2017,"finding":"CREBH directly binds CREBH-recognition sites in the TGF-β2 promoter to induce TGF-β2 transcription in HCV-infected hepatocytes. Active nuclear CREBH accumulates during HCV infection, and CREBH silencing reduces TGF-β2 expression and fibrogenic responses in hepatic stellate cells.","method":"EMSA, ChIP, promoter-luciferase, siRNA knockdown, CREBH null mouse model, co-culture of HCV-infected cells with HSCs","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — EMSA and ChIP confirm direct CREBH-TGF-β2 promoter binding; loss-of-function in cells and in vivo null mouse","pmids":["28621467"],"is_preprint":false},{"year":2017,"finding":"GSK-3 phosphorylation of the P-motif (S73–S90) of the full-length CREB-H precursor promotes ER retention and prevents ER-to-Golgi transport; mutation of these serines or pharmacological GSK-3 inhibition causes constitutive Golgi transport, proteolytic cleavage, and nuclear import. The same P-motif in the nuclear product is also phosphorylated by GSK-3/CKII to target CREB-H for SCF-mediated degradation, providing integrated control coupling ER-to-Golgi transport with nuclear stability.","method":"GSK-3 inhibitor treatment, serine-to-alanine mutagenesis, phosphospecific antibody, immunofluorescence, nuclear fractionation, transcriptional assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — integrated phosphorylation-mutagenesis approach showing coupled control of transport and stability; extends and confirms PMID 26108621","pmids":["28381424"],"is_preprint":false},{"year":2018,"finding":"The Sel1L–HRD1 ERAD complex regulates ubiquitination and proteasomal turnover (and thus nuclear abundance) of CREBH in the liver. Liver-specific Sel1L deletion elevates CREBH nuclear levels and dramatically increases FGF21 expression; this is specifically through CREBH (not PPARα). An inverse correlation between Sel1L–HRD1 ERAD activity and CREBH–FGF21 levels was demonstrated across fasting-feeding cycles.","method":"Liver-specific Sel1L KO mice, ubiquitination assay, Co-IP, FGF21 measurement, CREBH protein stability assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent groups (PMID 30389665, PMID 30389664) using genetic KO plus ubiquitination assays demonstrating ERAD-mediated CREBH turnover","pmids":["30389665"],"is_preprint":false},{"year":2018,"finding":"HRD1 E3 ligase mediates K48-linked polyubiquitin conjugation onto CREBH at lysine 294 (K294) for proteasomal degradation to downregulate FGF21 expression. Liver-specific HRD1 deletion phenocopies FGF21 gain-of-function mice (growth retardation, female infertility, circadian disruption).","method":"Liver-specific HRD1 KO mice, ubiquitin site-mapping at K294, ubiquitination assay, FGF21/CREBH protein turnover assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific ubiquitination at K294 identified biochemically; in vivo genetic model phenocopies CREBH gain-of-function; replicated in PMID 30389665","pmids":["30389664"],"is_preprint":false},{"year":2019,"finding":"CREBH activates expression of key autophagy genes (LC3, ATG7, ATG2b, ULK1) and lysosomal biogenesis genes in the liver upon starvation or energy-demanding circadian phases. CREBH deficiency reduces hepatic autophagic activity and increases lipid accumulation upon starvation. Under starvation, CREBH interacts with PPARα and PGC-1α to synergistically drive autophagy gene expression.","method":"CREBH KO mouse phenotyping, autophagy flux assay, Co-IP (CREBH–PPARα–PGC-1α), ChIP, gene expression analysis, adenoviral CREBH overexpression","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse autophagy phenotype plus Co-IP of complex plus ChIP on autophagy gene promoters; multiple orthogonal methods","pmids":["30912978"],"is_preprint":false},{"year":2020,"finding":"N-glycosylation of CREBH enhances its proteolytic activation and transcriptional capacity. N-glycosylation modulates CREBH's ability to activate PPARα and SCD-1 promoters via protein interactions. Deglycosylated CREBH shows impaired proteolysis (PA-induced cleavage blocked by tunicamycin), increased lipogenesis, and lipotoxicity in cells and NAFLD mouse models.","method":"Glycosylation site mutagenesis, GnT-V hyperglycosylation, tunicamycin treatment, Co-IP (CREBH–PPARα, CREBH–SCD-1), promoter-luciferase, lentivirus injection mouse model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus Co-IP plus in vivo lentivirus model; single lab; extends earlier glycosylation finding (PMID 20356926)","pmids":["32996649"],"is_preprint":false},{"year":2020,"finding":"Full-length CREBH in the ER physically interacts with SREBP proteins and promotes formation of the SREBP-INSIG1 complex, retaining SREBP in the ER and preventing its proteolytic activation at the Golgi. CREBH deficiency leads to accumulation of nuclear SREBP, thereby de-repressing lipogenic/cholesterogenic gene expression.","method":"Co-IP (CREBH–SREBP–INSIG1), nuclear/cytoplasmic fractionation of SREBP, CREBH KO and liver/intestine-specific KO mouse lipid phenotyping","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes direct interaction; KO phenotype consistent with mechanism; single lab, needs independent replication","pmids":["33246135"],"is_preprint":false},{"year":2021,"finding":"The HRD1/Sel1L ERAD complex mediates circadian polyubiquitination and degradation of CREBH protein across the circadian cycle; HRD1 and Sel1L expression itself is rhythmically driven by CREBH–PPARα–BMAL1. HRD1 liver-specific KO increases CREBH levels, altering circadian TG, FA, and glucose profiles; suppressing CREBH overproduction in HRD1 LKO mice rescues diurnal lipid profiles.","method":"Liver-specific HRD1 KO and CREBH KO mice, circadian metabolite profiling, ubiquitination assay, Co-IP (CREBH–PPARα–BMAL1), rescue by CREBH suppression in HRD1 LKO","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (rescue of HRD1 KO phenotype by CREBH suppression) combined with biochemical ubiquitination assay and protein interaction data; multiple methods","pmids":["33592335"],"is_preprint":false},{"year":2023,"finding":"The C-terminal fragment of CREBH (CREBH-C), derived from cleavage of full-length CREBH, is secreted as a hepatokine in response to fasting or hepatic stress. CaMKII-mediated phosphorylation of CREBH-C is required for its efficient secretion via exocytosis. Secreted CREBH-C blocks formation of the ANGPTL3–ANGPTL8 inhibitory complex, thereby increasing LPL activity in plasma and metabolic tissues, promoting triglyceride clearance.","method":"CREBH-C detection in conditioned media and plasma, CaMKII inhibitor and kinase assay, ANGPTL3–ANGPTL8 Co-IP in presence of CREBH-C, LPL activity assay in vivo, CREBH-C administration to high-fat diet mice","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical identification of secreted fragment, kinase requirement for secretion, Co-IP demonstrating ANGPTL3/8 complex disruption, and in vivo phenotypic rescue; multiple orthogonal methods","pmids":["36649378"],"is_preprint":false},{"year":2021,"finding":"CREBH normalizes diabetic dyslipidemia via an APOE-dependent mechanism: active CREBH enriches APOE on TRL remnants and depletes APOC3, promoting hepatic clearance of remnant lipoproteins. This mechanism is independent of LPL (confirmed in LPL-deficient mice) but requires APOE (fails in Apoe-/- mice).","method":"LPL-deficient and Apoe-/- mouse genetic models with CREBH adenoviral expression, lipoprotein particle profiling, apolipoprotein composition analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent genetic epistasis models (LPL KO and APOE KO) to dissect mechanism; rigorous lipoprotein characterization","pmids":["34491909"],"is_preprint":false},{"year":2022,"finding":"CREBH promotes SIRT3 expression, which deacetylates MnSOD to reduce mitochondrial oxidative stress and inhibits NLRP3 inflammasome activation. CREBH overexpression alleviates mitochondrial oxidative stress in NASH; SIRT3 suppression abolishes this protective effect; CREBH KO mice show elevated oxidative stress and NASH susceptibility.","method":"Co-IP (SIRT3–CPT2, SIRT3–ACADL interaction), acetylation assay of MnSOD, NLRP3 inflammasome activation measurement, CREBH KO and OE mouse/cell models","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and acetylation assay link CREBH→SIRT3→MnSOD deacetylation; single lab, needs replication","pmids":["35926687"],"is_preprint":false},{"year":2024,"finding":"CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion under energy demands. Activated CREBH, cooperating with PPARα, drives expression of UPRmt regulators ATF5 and ATF4. CREBH deficiency causes accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and shifts energy metabolism from fatty acid oxidation toward carbohydrate oxidation.","method":"MAM fractionation, CREBH KO mouse phenotyping, mitochondrial membrane potential assay, mitochondrial unfolded protein detection, Co-IP (CREBH–PPARα), gene expression analysis, metabolic flux measurement","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — subcellular fractionation showing MAM localization plus genetic KO phenotype plus Co-IP plus mechanistic ATF5/ATF4 target gene analysis; multiple orthogonal methods","pmids":["39589874"],"is_preprint":false},{"year":2015,"finding":"TNFα induces CREBH expression via NF-κB signaling in osteoblasts; active CREBH increases Smurf1 expression leading to ubiquitin-dependent degradation of Smad1, thereby inhibiting BMP2-induced osteoblast differentiation. CREBH knockdown attenuates TNFα-mediated Smad1 degradation and rescues osteoblast differentiation.","method":"Co-IP (Smad1–Smurf1), siRNA knockdown, adenoviral CREBH overexpression, ALP/osteocalcin assays, ectopic bone formation in vivo","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and loss-of-function establish CREBH→Smurf1→Smad1 degradation pathway; single lab","pmids":["25873397"],"is_preprint":false},{"year":2013,"finding":"Hepatic CREBH is a positive transcriptional regulator of CYP2B family genes (e.g., CYP2B10); CREBH ectopic expression increases CYP2B10 promoter activity, and CREBH-deficient mice show severely impaired CYP2B induction and resistance to sulpyrine-induced fatal shock. Reintroduction of CYP2B into CREBH-deficient liver restores sulpyrine susceptibility.","method":"Promoter-luciferase assay, CREBH KO mouse, in vivo knockdown (siRNA), adenoviral CYP2B rescue","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus genetic rescue in vivo; single lab, phenotypic but mechanistic pathway clearly defined","pmids":["23409047"],"is_preprint":false},{"year":2025,"finding":"CREB-H induces expression of Cgref1 (a secreted hepatokine) via direct transcriptional regulation. Secreted Cgref1 suppresses insulin signaling and glucose uptake in epididymal white adipose tissue, creating eWAT insulin resistance that in turn promotes hepatic de novo lipogenesis.","method":"Microarray of Creb3l3-/- mice, Cgref1 KO mice, transcriptomic/metabolomic/lipidomic analysis, gain/loss-of-function in hepatocytes, insulin signaling assay in eWAT","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model combined with multi-omics; single lab; specific CREBH-binding to Cgref1 promoter not directly verified by ChIP in abstract","pmids":["40303310"],"is_preprint":false},{"year":2025,"finding":"In zebrafish creb3l3 double mutants (lacking both orthologs), key creb3l3 target genes apoC2 and apoA4 are downregulated in intestines; mutants show impaired lipoprotein turnover (not reduced total lipoprotein production) and increased enterocyte lipid droplet size and number, establishing creb3l3 as a regulator of postprandial intestinal lipid flux balancing storage vs. secretion.","method":"Zebrafish genetic KO (CRISPR), lipoprotein reporter lines, histological lipid droplet analysis, gene expression analysis","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vertebrate model with defined lipoprotein and gene expression readouts; ortholog study","pmids":["40449732"],"is_preprint":false},{"year":2023,"finding":"CREBH promotes autophagic flux by transcriptionally repressing Coronin 1a (Coro1a), a gene that inhibits autophagosome-lysosome fusion. Overexpression of Coro1a in hepatocytes blocks autophagic flux; CREBH deficiency aggravates dysfunctional autophagy and liver injury in NASH.","method":"Autophagic flux assay (LC3-II, p62), lysosomal marker (LAMP1) imaging, CREBH KO in NASH mouse models, Coro1a promoter reporter, adenoviral Coro1a overexpression","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional target identification with reporter plus KO phenotype plus functional Coro1a rescue; single lab","pmids":["37837948"],"is_preprint":false}],"current_model":"CREBH (CREB3L3) is an ER-tethered, liver- and intestine-enriched bZIP transcription factor that is activated by regulated intramembrane proteolysis (RIP) at the Golgi by S1P/S2P proteases, releasing an N-terminal fragment that translocates to the nucleus; ER retention is mediated by a cytoplasmic ERM motif (not lumenal BiP binding as in ATF6), forward ER-to-Golgi transport is gated by GSK-3β phosphorylation of a serine-rich P-motif, and the active nuclear fragment is rapidly degraded via K48-linked polyubiquitination by SCF(β-TrCP/Fbw1a) or HRD1 ERAD-mediated K294 ubiquitination, with the balance between ERAD and productive cleavage controlled by cellular stress load; PCAF-mediated acetylation at K294 and SIRT1-mediated deacetylation modulate CREBH transcriptional potency and its interaction with PPARα; the active form drives hepatic acute-phase response (CRP, SAP), gluconeogenesis (PEPCK, G6Pase), fatty acid oxidation, ketogenesis, apolipoprotein (ApoA-I, ApoA-IV, ApoA-V, ApoC-II) and FGF21 expression—the latter through a CREBH–PPARα heterodimeric complex binding composite CRE–PPRE elements—while the C-terminal cleavage fragment is secreted as a hepatokine (CREBH-C) that disrupts the ANGPTL3–ANGPTL8 complex to activate lipoprotein lipase and promote triglyceride clearance; CREBH also regulates hepatic autophagy, mitochondrial unfolded protein response, VLDL assembly via apoB, and competes with SREBPs for ER-to-Golgi transport, collectively maintaining systemic lipid, glucose, and energy homeostasis across fasting-feeding and circadian cycles."},"narrative":{"mechanistic_narrative":"CREB3L3 (CREBH) is a liver- and intestine-enriched, ER-tethered bZIP transcription factor that functions as a master regulator of systemic lipid, glucose, and energy homeostasis across fasting-feeding and circadian cycles [PMID:11353085, PMID:20374965, PMID:27982131, PMID:28461393]. Like other CREB3-family factors it is synthesized as a membrane-anchored precursor and activated by regulated intramembrane proteolysis: ER stress or stimulation triggers cleavage by Golgi site-1 and site-2 proteases, liberating an N-terminal fragment that enters the nucleus and binds CRE, box-B, and ATF6 elements to drive transcription [PMID:11353085, PMID:15800215, PMID:16469704]. Multiple layers control this activation. ER retention is set by a cytoplasmic ERM determinant rather than lumenal BiP binding as in ATF6, and N-linked glycosylation of three lumenal sites is required for efficient proteolytic activation [PMID:17875199, PMID:19883396, PMID:20356926]. GSK-3β/CKII phosphorylation of a serine-rich P-motif both restrains ER-to-Golgi transport by gating COPII association and, in the nuclear product, primes the SDSGIS phosphodegron for SCF(β-TrCP/Fbw1a)-mediated K48 polyubiquitination and proteasomal turnover, while the Sel1L–HRD1 ERAD complex degrades the precursor and active fragment via K294 ubiquitination—coupling transport, stability, and circadian timing through BMAL1 [PMID:27029215, PMID:26108621, PMID:27507854, PMID:28381424, PMID:30389665, PMID:30389664, PMID:33592335]. Transcriptional potency is further tuned by PCAF-mediated K294 acetylation and SIRT1 deacetylation, which licenses a CREBH–PPARα heterodimeric complex that binds composite CRE–PPRE elements [PMID:24424044, PMID:26438600]. Through this axis CREBH drives the hepatic acute-phase response (CRP, SAP), gluconeogenesis (PEPCK, G6Pase) and glycogenolysis, fatty acid oxidation and ketogenesis, autophagy and lysosomal biogenesis, the mitochondrial unfolded protein response, and an extensive lipoprotein program including ApoA-IV, ApoA-I, FGF21, and intestinal cholesterol handling via Npc1l1 [PMID:16469704, PMID:20374965, PMID:24424044, PMID:24598141, PMID:27982131, PMID:27417587, PMID:27818935, PMID:28461393, PMID:30912978, PMID:39589874]. Its secreted C-terminal hepatokine fragment disrupts the ANGPTL3–ANGPTL8 complex to activate lipoprotein lipase and clear triglycerides, and active CREBH additionally normalizes dyslipidemia through an APOE-dependent remodeling of remnant lipoproteins [PMID:36649378, PMID:34491909]. Full-length ER-resident CREBH also restrains lipogenesis by sequestering SREBP in the SREBP–INSIG1 complex [PMID:33246135].","teleology":[{"year":2001,"claim":"Established CREBH as a liver-specific, ER-membrane-anchored bZIP factor whose activation depends on release from the membrane, defining the basic regulatory logic of a latent transcription factor.","evidence":"GFP imaging, EMSA, GAL4 transactivation and luciferase reporters with transmembrane-domain deletion","pmids":["11353085"],"confidence":"High","gaps":["Did not identify the protease or the physiological activating stimulus","DNA-target gene program in vivo not defined"]},{"year":2006,"claim":"Identified the activating proteolysis as S1P/S2P cleavage at the Golgi upon ER stress and linked CREBH to the hepatic acute-phase response, converting a localization observation into a defined signaling pathway.","evidence":"In vivo cleavage assay, siRNA knockdown, SAP/CRP promoter reporters, LPS/cytokine challenge in mice","pmids":["16469704"],"confidence":"High","gaps":["How proinflammatory signals are transduced to the cleavage machinery not resolved","Did not address ER-retention determinant"]},{"year":2007,"claim":"Showed CREBH partitions between ERAD-mediated degradation and the productive cleavage pathway, establishing a stress-tuned switch governing how much active factor is produced.","evidence":"Subcellular fractionation, proteasome inhibition, glycosylation analysis, ERM-deletion mutagenesis","pmids":["17875199"],"confidence":"High","gaps":["E3 ligase mediating basal ERAD not identified at this stage","Cellular signals biasing the switch undefined"]},{"year":2010,"claim":"Defined the distinct ER-retention mechanism (cytoplasmic ERM, not lumenal BiP) and a glycosylation requirement for activation, separating CREBH mechanistically from ATF6.","evidence":"Domain swap/deletion mutagenesis, BiP co-IP, glycosylation-site mutants with reporter readout","pmids":["19883396","20356926"],"confidence":"High","gaps":["The trafficking machinery reading the ERM not identified","Why glycosylation is required for cleavage mechanistically unresolved"]},{"year":2010,"claim":"Connected CREBH to hepatic glucose output via direct binding of gluconeogenic promoters and a PPARα-driven feed-forward induction loop, placing it in fasting metabolic control.","evidence":"ChIP, EMSA, promoter reporters, adenoviral/siRNA manipulation and blood-glucose phenotyping in mice; PPARα PPRE in the CREBH promoter","pmids":["20374965","20006574"],"confidence":"High","gaps":["Whether glucose effect is fully cell-autonomous in hepatocytes vs systemic not separated","Coactivator requirements only partially defined"]},{"year":2011,"claim":"Identified upstream inputs and a repressor controlling CREBH activity, showing endocannabinoid/CB1R–JNK signaling induces CREBH and SMILE competes with PGC-1α to dampen it.","evidence":"ChIP, promoter mutagenesis, co-IP/GST pulldown, glucose-production assays in hepatocytes","pmids":["21693703","21994947"],"confidence":"High","gaps":["Quantitative balance of activators vs SMILE repression in vivo unclear","CB1R-to-CREBH signaling steps between JNK and promoter incompletely mapped"]},{"year":2014,"claim":"Resolved CREBH–PPARα as a binary complex binding composite CRE–PPRE elements and identified direct apolipoprotein targets, establishing the molecular basis of its lipid/FGF21 transcriptional output.","evidence":"Reciprocal co-IP, ChIP at the FGF21 promoter, EMSA at Apoa4 sites, gain/loss-of-function in mice","pmids":["24424044","24598141"],"confidence":"High","gaps":["Stoichiometry and structural architecture of the CREBH–PPARα complex unknown","Full genome-wide target set not defined"]},{"year":2015,"claim":"Defined post-translational tuning of CREBH: PCAF/SIRT1 acetylation at K294 licenses PPARα partnership, while GSK-3/CKII phosphorylation of the P-motif and an SDSGIS phosphodegron target the nuclear form for SCF(β-TrCP/Fbw1a) degradation.","evidence":"Site-directed mutagenesis, co-IP, in vitro kinase assays, ubiquitination assays, in vivo K294R mutant phenotyping","pmids":["26438600","26108621","27029215"],"confidence":"High","gaps":["How acetylation and phosphorylation are coordinated on the same molecule unresolved","Kinase/acetyltransferase recruitment mechanism not defined"]},{"year":2016,"claim":"Integrated CREBH activation into circadian physiology, showing BMAL1/GSK3β-gated COPII-dependent transport rhythmically controls cleavage, and demonstrated genetically separable contributions to fatty acid oxidation/ketogenesis.","evidence":"Circadian cleavage profiling, BMAL1 KO, GSK3β inhibition, COPII co-IP; Creb3l3/Ppara double-KO epistasis","pmids":["27507854","27982131"],"confidence":"High","gaps":["Direct PPARα-independent target genes for oxidation not fully enumerated","Mechanism linking GSK3β phosphorylation to COPII selection incomplete"]},{"year":2016,"claim":"Extended CREBH to lipoprotein and cholesterol homeostasis in liver and intestine, directly activating Apoa1 and Fsp27β and repressing intestinal Npc1l1.","evidence":"Reporter assays, reciprocal tissue-specific transgenic and KO mouse models with lipid/atherosclerosis phenotyping","pmids":["27417587","25125366","27818935"],"confidence":"High","gaps":["Tissue-specific cofactors distinguishing hepatic vs intestinal programs unclear","Fsp27β (lipid storage) vs apolipoprotein (clearance) balance not reconciled"]},{"year":2017,"claim":"Mapped additional upstream control (TLR/MyD88–TRAF6 K63-ubiquitination promoting cleavage) and expanded function to circadian glucose homeostasis, fibrogenic TGF-β2, and CYP2B drug metabolism.","evidence":"Co-IP, linkage-specific ubiquitination assays, ChIP, KO mouse phenotyping across inflammatory, glucose, fibrosis and xenobiotic readouts","pmids":["27637329","28461393","28621467","23409047"],"confidence":"High","gaps":["How K63 ubiquitination mechanistically facilitates cleavage unresolved","Interplay between inflammatory and metabolic activation inputs not integrated"]},{"year":2017,"claim":"Unified P-motif phosphorylation as a dual-purpose control, gating ER-to-Golgi transport of the precursor and the stability of the nuclear product, coupling activation amplitude to nuclear lifetime.","evidence":"GSK-3 inhibition, serine-to-alanine mutagenesis, phosphospecific antibody, fractionation and transcription assays","pmids":["28381424"],"confidence":"High","gaps":["Spatial separation of the two P-motif functions not fully resolved","Phosphatase counter-regulation unknown"]},{"year":2018,"claim":"Identified the Sel1L–HRD1 ERAD complex as the dominant E3 system controlling CREBH abundance via K294 K48-ubiquitination, with FGF21 as a key output, defining a stress/feeding-tuned protein-stability rheostat.","evidence":"Liver-specific Sel1L and HRD1 KO mice, K294 ubiquitin site-mapping, co-IP, stability assays, FGF21 measurement (two groups)","pmids":["30389665","30389664"],"confidence":"High","gaps":["Relationship between K294 ubiquitination and K294 acetylation on the same residue not mechanistically reconciled","How ERAD selects CREBH among substrates unclear"]},{"year":2019,"claim":"Established CREBH as a transcriptional driver of hepatic autophagy and lysosomal biogenesis acting with PPARα/PGC-1α, broadening its catabolic role beyond gene-by-gene metabolic targets.","evidence":"KO mouse autophagy-flux phenotyping, co-IP of the CREBH–PPARα–PGC-1α complex, ChIP on autophagy gene promoters","pmids":["30912978"],"confidence":"High","gaps":["Direct vs indirect regulation of individual ATG genes not fully separated","Coordination with mTOR/TFEB autophagy control unknown"]},{"year":2020,"claim":"Revealed a non-transcriptional ER function: full-length CREBH retains SREBP via the SREBP–INSIG1 complex, positioning CREBH as a brake on lipogenesis in addition to its nuclear catabolic program.","evidence":"Co-IP, SREBP nuclear/cytoplasmic fractionation, KO and tissue-specific KO lipid phenotyping; glycosylation modulation of activation","pmids":["33246135","32996649"],"confidence":"Medium","gaps":["Single-lab interaction data awaits independent replication","Whether precursor sequestration competes quantitatively with cleavage in vivo unresolved"]},{"year":2021,"claim":"Demonstrated mechanistic specificity in triglyceride clearance: CREBH normalizes diabetic dyslipidemia through APOE-dependent remnant clearance (LPL-independent), and circadian HRD1/Sel1L turnover of CREBH shapes diurnal lipid/glucose profiles.","evidence":"LPL-deficient and Apoe-/- genetic epistasis with CREBH adenovirus; HRD1/CREBH KO circadian metabolite profiling with rescue","pmids":["34491909","33592335"],"confidence":"High","gaps":["How CREBH alters APOE/APOC3 ratios on particles mechanistically unclear","Reconciliation of LPL-dependent (hepatokine) and LPL-independent (APOE) clearance routes incomplete"]},{"year":2023,"claim":"Identified the secreted C-terminal hepatokine CREBH-C as an endocrine effector, showing CaMKII-dependent secretion and disruption of the ANGPTL3–ANGPTL8 complex to activate LPL, giving the C-terminal fragment its own signaling function.","evidence":"Conditioned-media/plasma detection, CaMKII inhibition/kinase assay, ANGPTL3–ANGPTL8 co-IP, in vivo LPL activity and CREBH-C administration","pmids":["36649378"],"confidence":"High","gaps":["Receptor or surface engagement of CREBH-C at peripheral tissues unknown","Relative contribution of CREBH-C vs nuclear CREBH to lipid lowering not quantified"]},{"year":2024,"claim":"Linked CREBH to mitochondrial proteostasis and contact-site biology, showing it expands MAMs and, with PPARα, drives the UPRmt regulators ATF5/ATF4 to sustain fatty acid oxidation.","evidence":"MAM fractionation, KO mouse phenotyping, membrane-potential and unfolded-protein assays, co-IP, metabolic flux","pmids":["39589874"],"confidence":"High","gaps":["Mechanism by which CREBH promotes MAM expansion not defined","Direct ChIP evidence at ATF5/ATF4 loci not detailed"]},{"year":2025,"claim":"Expanded the inter-organ output of CREBH, identifying secreted hepatokine Cgref1 as a mediator of adipose insulin resistance and confirming conserved intestinal lipid-flux control in zebrafish.","evidence":"Creb3l3-/- multi-omics and Cgref1 KO mice; zebrafish creb3l3 double mutants with lipoprotein reporters and lipid-droplet analysis","pmids":["40303310","40449732"],"confidence":"Medium","gaps":["Direct ChIP confirmation of CREBH binding at the Cgref1 promoter lacking","Whether intestinal mechanism in fish fully translates to mammalian enterocytes untested"]},{"year":null,"claim":"How the competing fates of CREBH—ERAD degradation, productive RIP cleavage, SREBP sequestration, and C-terminal hepatokine secretion—are quantitatively coordinated by a single stress/feeding/circadian input remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No integrated model partitioning precursor flux among ERAD, cleavage, and SREBP retention","Structural basis of CREBH–PPARα complex and its acetylation-dependent assembly unknown","Receptors for secreted CREBH-C and Cgref1 unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,7,12,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,13,24]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[30,32]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3,5,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,7]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[35]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[32]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,19,20,21,22,33]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,12,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,3,35]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[16,17,26,27,31]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[28,40]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[18,22,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,23]}],"complexes":["CREBH–PPARα transcriptional complex","SCF(β-TrCP/Fbw1a) E3 ligase complex (substrate)","Sel1L–HRD1 ERAD complex (substrate)","SREBP–INSIG1 complex (associated)"],"partners":["PPARA","SREBF (SREBP)","INSIG1","BTRC (Β-TRCP/FBW1A)","HRD1 (SYVN1)","SEL1L","TRAF6","CREBZF (SMILE)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q68CJ9","full_name":"Cyclic AMP-responsive element-binding protein 3-like protein 3","aliases":["Transcription factor CREB-H"],"length_aa":461,"mass_kda":49.1,"function":"Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes. Activated in response to cAMP stimulation. In vitro, binds to the cAMP response element (CRE) and box-B element. Activates transcription through box-B element. Activates transcription through CRE (By similarity). May function synergistically with ATF6. In acute inflammatory response, may activate expression of acute phase response (APR) genes. May be involved in growth suppression. Regulates FGF21 transcription (By similarity). Plays a crucial role in the regulation of triglyceride metabolism and is required for the maintenance of normal plasma triglyceride concentrations (PubMed:21666694)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q68CJ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CREB3L3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CREB3L3","total_profiled":1310},"omim":[{"mim_id":"619324","title":"HYPERTRIGLYCERIDEMIA 2; HYTG2","url":"https://www.omim.org/entry/619324"},{"mim_id":"611998","title":"cAMP RESPONSE ELEMENT-BINDING PROTEIN 3-LIKE 3; CREB3L3","url":"https://www.omim.org/entry/611998"},{"mim_id":"607402","title":"INTERFERON, LAMBDA-3; IFNL3","url":"https://www.omim.org/entry/607402"},{"mim_id":"607138","title":"cAMP RESPONSE ELEMENT-BINDING PROTEIN 3-LIKE 4; CREB3L4","url":"https://www.omim.org/entry/607138"},{"mim_id":"602329","title":"SUPPRESSOR OF LIN12-LIKE; SEL1L","url":"https://www.omim.org/entry/602329"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":242.2},{"tissue":"liver","ntpm":381.3}],"url":"https://www.proteinatlas.org/search/CREB3L3"},"hgnc":{"alias_symbol":["CREB-H","CREBH"],"prev_symbol":[]},"alphafold":{"accession":"Q68CJ9","domains":[{"cath_id":"1.20.5","chopping":"212-315","consensus_level":"medium","plddt":90.5916,"start":212,"end":315}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68CJ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q68CJ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q68CJ9-F1-predicted_aligned_error_v6.png","plddt_mean":58.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CREB3L3","jax_strain_url":"https://www.jax.org/strain/search?query=CREB3L3"},"sequence":{"accession":"Q68CJ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q68CJ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q68CJ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68CJ9"}},"corpus_meta":[{"pmid":"16469704","id":"PMC_16469704","title":"Endoplasmic 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Full-length GFP-CREBH localizes to perinuclear reticular structures, while the TM-deleted mutant localizes to the nucleus. CREBH binds CRE and box-B elements but not C/EBP, AP-1, or NF-κB elements.\",\n      \"method\": \"GFP fusion live imaging, gel mobility shift assay, GAL4 fusion transactivation assay, luciferase reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, EMSA, reporter assay, deletion mutagenesis) in a single rigorous study establishing localization and DNA-binding specificity\",\n      \"pmids\": [\"11353085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CREB-H is activated by proteolytic cleavage that removes the C-terminal transmembrane domain, releasing a nuclear fragment. The active form binds to CRE, box-B, and ATF6-binding elements and activates the PEPCK-C promoter; this activation is further stimulated by cAMP and protein kinase A.\",\n      \"method\": \"Luciferase reporter assay, co-immunoprecipitation, promoter activation assay, cell proliferation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in a single study; replication of cleavage/nuclear translocation mechanism consistent with other papers\",\n      \"pmids\": [\"15800215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Upon ER stress, CREBH is cleaved by site-1 protease (S1P) and site-2 protease (S2P) at the Golgi to liberate an N-terminal fragment that translocates to the nucleus and activates transcription of acute phase response genes SAP and CRP. Proinflammatory cytokines (and LPS) induce CREBH expression and trigger its cleavage in vivo.\",\n      \"method\": \"In vivo cleavage assay, siRNA knockdown, promoter-luciferase reporter, mouse LPS/cytokine challenge\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic cleavage by defined proteases confirmed in vitro and in vivo with loss-of-function, replicated across multiple subsequent studies\",\n      \"pmids\": [\"16469704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CREB-H is subject to N-linked glycosylation and undergoes ERAD: it is retrotranslocated from the ER to the cytosol, deglycosylated, and degraded by the proteasome under basal conditions. Proteasome inhibition diverts CREB-H from ERAD into the cleavage/nuclear-transport pathway. A cytoplasmic determinant (ERM) mediates ER retention; deletion of this motif causes constitutive Golgi localization and cleavage.\",\n      \"method\": \"Subcellular fractionation, proteasome inhibitor treatment, glycosylation analysis, deletion mutagenesis, nuclear transport assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and cell biological methods; competition between ERAD and RIP pathways mechanistically established\",\n      \"pmids\": [\"17875199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PPARα directly binds to a PPRE in the CREBH promoter to induce CREBH expression in response to fatty acids and fasting. CREBH mRNA and nuclear protein are induced by fasting and suppressed by refeeding; this suppression is impaired in ob/ob mice.\",\n      \"method\": \"Luciferase reporter assay, EMSA, ChIP assay, promoter deletion analysis, PPARα agonist/antagonist treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EMSA and ChIP identify direct PPARα binding to CREBH promoter; supported by pharmacological gain/loss-of-function\",\n      \"pmids\": [\"20006574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Unlike ATF6, whose ER retention is mediated by lumenal BiP binding, CREB-H ER retention is controlled by a membrane-proximal cytoplasmic determinant (ERM) conserved in the CREB3 family but absent in ATF6. The lumenal tail of CREB-H neither binds BiP nor is required for ER retention or Golgi transport; ERM deletion causes constitutive Golgi localization and cleavage by S1P.\",\n      \"method\": \"Domain deletion and swap mutagenesis, co-IP for BiP binding, fluorescence microscopy, constitutive cleavage assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-style domain-swap experiment with mutagenesis clearly dissects distinct ER-retention mechanism vs ATF6\",\n      \"pmids\": [\"19883396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"N-linked glycosylation of CREB-H at three luminal sites is required for its efficient proteolytic activation. Unglycosylated CREB-H mutant (all three N-glycosylation sites abolished) is retained in an inactive ER form and fails to be cleaved or activate transcription in response to S1P stimulation.\",\n      \"method\": \"Site-directed mutagenesis of glycosylation sites, brefeldin A / KDEL-S1P stimulation, transcription reporter assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple glycosylation site mutants characterized with functional transcription readouts; consistent with parallel ERAD study\",\n      \"pmids\": [\"20356926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CREBH regulates hepatic gluconeogenesis: it is induced by fasting or insulin-resistant state in a dexamethasone- and PGC-1α-dependent manner; the active nuclear form (CREBH-N) binds an enhancer in the PEPCK-C and G6Pase promoters distinct from the classical CREB/CRTC2 sites; hepatic CREBH knockdown reduces blood glucose in mice.\",\n      \"method\": \"Adenoviral overexpression, siRNA knockdown, ChIP assay, promoter-luciferase, glucose tolerance/blood glucose measurement in mice\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ChIP showing CREBH binding to gluconeogenic promoters combined with in vivo knockdown phenotype; replicated by subsequent studies\",\n      \"pmids\": [\"20374965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CB1R activation by 2-AG induces CREBH gene expression via JNK phosphorylation and c-Jun binding to an AP-1 site in the CREBH promoter. CREBH mediates CB1R-stimulated hepatic gluconeogenic gene expression and glucose production; endogenous CREBH knockdown abolishes 2-AG-induced gluconeogenesis.\",\n      \"method\": \"ChIP assay, promoter mutagenesis-luciferase, siRNA knockdown, glucose production assay in primary hepatocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and promoter mutagenesis identify AP-1 site; loss-of-function abolishes phenotype in primary human and rat hepatocytes\",\n      \"pmids\": [\"21693703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SMILE (small heterodimer partner-interacting leucine zipper protein) interacts with CREBH via its bZIP domain and represses CREBH-mediated transactivation. SMILE competes with PGC-1α coactivation of CREBH; curcumin induces SMILE through LKB1/AMPK signaling to selectively inhibit CREBH (not ATF6) target gene transcription.\",\n      \"method\": \"Co-IP, GST pulldown, ChIP, Gal4 fusion transactivation, siRNA knockdown, dominant-negative assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP establishes direct protein–protein interaction; ChIP confirms competition on endogenous promoter; loss-of-function controls\",\n      \"pmids\": [\"21994947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CB1R agonist 2-AG induces Lipin1 gene expression in a CREBH-dependent manner; CREBH directly recruits to the Lipin1 promoter. This increases hepatic diacylglycerol levels and PKCε phosphorylation, thereby inhibiting insulin receptor signaling.\",\n      \"method\": \"ChIP assay, adenoviral CREBH overexpression/knockdown, DAG measurement, PKCε phosphorylation assay, insulin receptor signaling assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP shows CREBH binding to Lipin1 promoter; downstream PKCε/insulin signaling pathway defined by loss-of-function; single lab\",\n      \"pmids\": [\"22989885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CREB-H contains a unique ATB domain (absent in all other human bZIP factors) essential for transcriptional activity. CREB-H activates secretory pathway genes (SPGs) and stimulates secretion of specific cargo including apolipoproteins (ApoA-IV, ApoAI) in liver cells.\",\n      \"method\": \"Drosophila ATB domain complementation, deletion mutagenesis, transcriptomics, ELISA for secreted proteins\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain swap in heterologous system plus endogenous target gene and secretion readouts; single lab, multiple methods\",\n      \"pmids\": [\"23279168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CREBH and PPARα interact to form a functional binary transcriptional complex that binds integrated CRE–PPRE composite elements in the FGF21 promoter; PPARα requires CREBH to exert its trans-activation effect on FGF21. CREBH and PPARα mutually regulate each other's expression.\",\n      \"method\": \"Co-IP, ChIP, luciferase reporter, gain- and loss-of-function in mice (adenoviral and genetic), FGF21 protein measurement\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus ChIP demonstrating complex at endogenous FGF21 promoter; replicated in multiple subsequent studies\",\n      \"pmids\": [\"24424044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CREBH directly activates Apoa4 (apolipoprotein A-IV) transcription via two tandem CREBH-binding sites (5'-CCACGTTG-3') in the promoter conserved between human and mouse; CREBH protein is constitutively processed to its active form in normal liver, with further increase during steatosis.\",\n      \"method\": \"ChIP, EMSA, luciferase reporter, CREBH-deficient mouse transcriptomics\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and EMSA confirm direct binding; conserved binding site validated by mutagenesis; single lab\",\n      \"pmids\": [\"24598141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CREBH is acetylated at lysine 294 (K294) within its bZIP domain during fasting. PCAF mediates acetylation, SIRT1 mediates deacetylation. K294 acetylation is required for CREBH–PPARα interaction and synergistic transcriptional activation of lipid metabolic target genes; acetylation-deficient (K294R) mutant abolishes this interaction and causes hepatic steatosis in vivo.\",\n      \"method\": \"Site-directed mutagenesis, co-IP, luciferase reporter, adenoviral K294 mutant injection into mice, hepatic lipid measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis plus Co-IP plus in vivo phenotype; replicated in circadian study (PMID 28461393)\",\n      \"pmids\": [\"26438600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CREBH directly activates the Fsp27β (liver-specific isoform) promoter (not the Fsp27α/PPARγ-driven promoter). Fsp27β localizes to lipid droplets and suppresses lipolysis; CREBH-driven Fsp27β expression promotes lipid droplet enlargement and triglyceride accumulation in the liver.\",\n      \"method\": \"Promoter-luciferase assay, adenoviral overexpression/KO mouse, Oil-Red-O staining, lipid droplet imaging\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter and in vivo KO/OE establish CREBH-specific regulation of Fsp27β; single lab\",\n      \"pmids\": [\"25125366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The active nuclear form of CREB-H (CREB-H-ΔTC) is degraded by the SCF(β-TrCP) E3 ubiquitin ligase via K48-linked polyubiquitination. β-TrCP binds a conserved phosphodegron motif SDSGIS in CREB-H-ΔTC; phosphorylation of this motif is required for β-TrCP recognition and subsequent proteasomal degradation.\",\n      \"method\": \"Co-IP, ubiquitination assay, site-directed mutagenesis, siRNA knockdown of β-TrCP, cycloheximide chase\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution of ubiquitination, mutagenesis of phosphodegron, multiple orthogonal stability assays; single lab\",\n      \"pmids\": [\"27029215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Phosphorylation of CREB-H within a serine-rich P-motif (around S87/S90) by CKII and GSK-3β targets CREB-H to the SCF(Fbw1a/β-TrCP) E3 ligase for proteasomal degradation. CREB-H directly interacts with Fbw1a in a phosphorylation-dependent manner; GSK-3 phosphorylation at adjacent serines primes subsequent CKII phosphorylation at S87/S90.\",\n      \"method\": \"In vitro kinase assay with CKII and GSK-3β, phosphospecific antibody, dominant-negative Cul1, Co-IP, site-directed mutagenesis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus mutagenesis plus dominant-negative E3 ligase; replicated by β-TrCP paper (PMID 27029215)\",\n      \"pmids\": [\"26108621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CREBH proteolytic activation exhibits circadian rhythmicity controlled by the core clock oscillator BMAL1 and AKT/GSK3β signaling. GSK3β-mediated phosphorylation of CREBH modulates its association with COPII vesicle components to control ER-to-Golgi transport and subsequent proteolytic cleavage in a circadian manner.\",\n      \"method\": \"Circadian profiling of CREBH cleavage in mouse livers, BMAL1 KO, GSK3β inhibitor, COPII co-IP, phosphorylation assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (BMAL1 KO) and pharmacological (GSK3β inhibitor) combined with biochemical COPII interaction assay; multiple orthogonal methods\",\n      \"pmids\": [\"27507854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hepatic CREB3L3 independently controls fatty acid oxidation and ketogenesis in addition to its role in activating PPARα in an auto-loop; double knockout (Creb3l3-/-/Ppara-/-) mice show further suppression of oxidation/ketogenesis genes beyond either single KO, indicating independent contributions.\",\n      \"method\": \"Creb3l3-/- and Ppara-/- single and double knockout mouse phenotyping on ketogenic diet and fasting; gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double-KO, replicated across fasting and ketogenic diet conditions\",\n      \"pmids\": [\"27982131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CREBH directly activates Apoa1 (apoA-I) gene transcription, contributing to HDL cholesterol production. CREBH deficiency in Ldlr-/- mice decreases HDL and apoA-I and accelerates atherosclerosis.\",\n      \"method\": \"Luciferase reporter assay, CREBH-deficient/Ldlr-/- double KO mouse phenotyping, lipid profiling\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus genetic loss-of-function with defined lipoprotein phenotype; single lab\",\n      \"pmids\": [\"27417587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Intestinal CREBH directly regulates Npc1l1 (cholesterol transporter) promoter activity to suppress intestinal cholesterol absorption; CREBH transgenic (intestine) mice show reduced Npc1l1 expression and decreased plasma/hepatic cholesterol, while CREBH null mice show the opposite.\",\n      \"method\": \"Promoter-luciferase assay, CREBH intestine-specific transgenic and global KO mice, cholesterol absorption measurement, fecal cholesterol output\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter reporter plus reciprocal genetic models (transgenic and KO) with defined mechanistic target gene\",\n      \"pmids\": [\"27818935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREBH maintains circadian glucose homeostasis by regulating glycogenolysis (via PYGL) and gluconeogenesis (via PCK1 and G6PC). CREBH interacts with PPARα, and K294 acetylation controls this interaction and synergistic gluconeogenic activity across the circadian cycle.\",\n      \"method\": \"CREBH KO mouse circadian phenotyping, Co-IP, adenoviral K294 acetylation-site mutants, glycogen measurement, blood glucose profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype plus Co-IP plus mutagenesis across multiple metabolic readouts; extends prior acetylation finding (PMID 26438600)\",\n      \"pmids\": [\"28461393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TLR/MyD88-dependent signaling activates CREBH in liver upon LPS. TRAF6 (E3 ubiquitin ligase, TLR mediator) interacts with CREBH in a MyD88-dependent manner and mediates K63-linked ubiquitination of CREBH to facilitate its cleavage and activation. Active CREBH then directly activates ApoA4 expression to modulate HDL.\",\n      \"method\": \"Co-IP (CREBH–TRAF6, CREBH–MyD88), K63-ubiquitination assay, ChIP on ApoA4 promoter, TLR/MyD88 KO mice, HDL measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and ubiquitination assay with linkage-specific antibody; genetic KO models confirming pathway; ChIP validates direct target\",\n      \"pmids\": [\"27637329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREBH directly binds CREBH-recognition sites in the TGF-β2 promoter to induce TGF-β2 transcription in HCV-infected hepatocytes. Active nuclear CREBH accumulates during HCV infection, and CREBH silencing reduces TGF-β2 expression and fibrogenic responses in hepatic stellate cells.\",\n      \"method\": \"EMSA, ChIP, promoter-luciferase, siRNA knockdown, CREBH null mouse model, co-culture of HCV-infected cells with HSCs\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EMSA and ChIP confirm direct CREBH-TGF-β2 promoter binding; loss-of-function in cells and in vivo null mouse\",\n      \"pmids\": [\"28621467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GSK-3 phosphorylation of the P-motif (S73–S90) of the full-length CREB-H precursor promotes ER retention and prevents ER-to-Golgi transport; mutation of these serines or pharmacological GSK-3 inhibition causes constitutive Golgi transport, proteolytic cleavage, and nuclear import. The same P-motif in the nuclear product is also phosphorylated by GSK-3/CKII to target CREB-H for SCF-mediated degradation, providing integrated control coupling ER-to-Golgi transport with nuclear stability.\",\n      \"method\": \"GSK-3 inhibitor treatment, serine-to-alanine mutagenesis, phosphospecific antibody, immunofluorescence, nuclear fractionation, transcriptional assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — integrated phosphorylation-mutagenesis approach showing coupled control of transport and stability; extends and confirms PMID 26108621\",\n      \"pmids\": [\"28381424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Sel1L–HRD1 ERAD complex regulates ubiquitination and proteasomal turnover (and thus nuclear abundance) of CREBH in the liver. Liver-specific Sel1L deletion elevates CREBH nuclear levels and dramatically increases FGF21 expression; this is specifically through CREBH (not PPARα). An inverse correlation between Sel1L–HRD1 ERAD activity and CREBH–FGF21 levels was demonstrated across fasting-feeding cycles.\",\n      \"method\": \"Liver-specific Sel1L KO mice, ubiquitination assay, Co-IP, FGF21 measurement, CREBH protein stability assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent groups (PMID 30389665, PMID 30389664) using genetic KO plus ubiquitination assays demonstrating ERAD-mediated CREBH turnover\",\n      \"pmids\": [\"30389665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HRD1 E3 ligase mediates K48-linked polyubiquitin conjugation onto CREBH at lysine 294 (K294) for proteasomal degradation to downregulate FGF21 expression. Liver-specific HRD1 deletion phenocopies FGF21 gain-of-function mice (growth retardation, female infertility, circadian disruption).\",\n      \"method\": \"Liver-specific HRD1 KO mice, ubiquitin site-mapping at K294, ubiquitination assay, FGF21/CREBH protein turnover assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific ubiquitination at K294 identified biochemically; in vivo genetic model phenocopies CREBH gain-of-function; replicated in PMID 30389665\",\n      \"pmids\": [\"30389664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CREBH activates expression of key autophagy genes (LC3, ATG7, ATG2b, ULK1) and lysosomal biogenesis genes in the liver upon starvation or energy-demanding circadian phases. CREBH deficiency reduces hepatic autophagic activity and increases lipid accumulation upon starvation. Under starvation, CREBH interacts with PPARα and PGC-1α to synergistically drive autophagy gene expression.\",\n      \"method\": \"CREBH KO mouse phenotyping, autophagy flux assay, Co-IP (CREBH–PPARα–PGC-1α), ChIP, gene expression analysis, adenoviral CREBH overexpression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse autophagy phenotype plus Co-IP of complex plus ChIP on autophagy gene promoters; multiple orthogonal methods\",\n      \"pmids\": [\"30912978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"N-glycosylation of CREBH enhances its proteolytic activation and transcriptional capacity. N-glycosylation modulates CREBH's ability to activate PPARα and SCD-1 promoters via protein interactions. Deglycosylated CREBH shows impaired proteolysis (PA-induced cleavage blocked by tunicamycin), increased lipogenesis, and lipotoxicity in cells and NAFLD mouse models.\",\n      \"method\": \"Glycosylation site mutagenesis, GnT-V hyperglycosylation, tunicamycin treatment, Co-IP (CREBH–PPARα, CREBH–SCD-1), promoter-luciferase, lentivirus injection mouse model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus Co-IP plus in vivo lentivirus model; single lab; extends earlier glycosylation finding (PMID 20356926)\",\n      \"pmids\": [\"32996649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Full-length CREBH in the ER physically interacts with SREBP proteins and promotes formation of the SREBP-INSIG1 complex, retaining SREBP in the ER and preventing its proteolytic activation at the Golgi. CREBH deficiency leads to accumulation of nuclear SREBP, thereby de-repressing lipogenic/cholesterogenic gene expression.\",\n      \"method\": \"Co-IP (CREBH–SREBP–INSIG1), nuclear/cytoplasmic fractionation of SREBP, CREBH KO and liver/intestine-specific KO mouse lipid phenotyping\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes direct interaction; KO phenotype consistent with mechanism; single lab, needs independent replication\",\n      \"pmids\": [\"33246135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The HRD1/Sel1L ERAD complex mediates circadian polyubiquitination and degradation of CREBH protein across the circadian cycle; HRD1 and Sel1L expression itself is rhythmically driven by CREBH–PPARα–BMAL1. HRD1 liver-specific KO increases CREBH levels, altering circadian TG, FA, and glucose profiles; suppressing CREBH overproduction in HRD1 LKO mice rescues diurnal lipid profiles.\",\n      \"method\": \"Liver-specific HRD1 KO and CREBH KO mice, circadian metabolite profiling, ubiquitination assay, Co-IP (CREBH–PPARα–BMAL1), rescue by CREBH suppression in HRD1 LKO\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (rescue of HRD1 KO phenotype by CREBH suppression) combined with biochemical ubiquitination assay and protein interaction data; multiple methods\",\n      \"pmids\": [\"33592335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The C-terminal fragment of CREBH (CREBH-C), derived from cleavage of full-length CREBH, is secreted as a hepatokine in response to fasting or hepatic stress. CaMKII-mediated phosphorylation of CREBH-C is required for its efficient secretion via exocytosis. Secreted CREBH-C blocks formation of the ANGPTL3–ANGPTL8 inhibitory complex, thereby increasing LPL activity in plasma and metabolic tissues, promoting triglyceride clearance.\",\n      \"method\": \"CREBH-C detection in conditioned media and plasma, CaMKII inhibitor and kinase assay, ANGPTL3–ANGPTL8 Co-IP in presence of CREBH-C, LPL activity assay in vivo, CREBH-C administration to high-fat diet mice\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical identification of secreted fragment, kinase requirement for secretion, Co-IP demonstrating ANGPTL3/8 complex disruption, and in vivo phenotypic rescue; multiple orthogonal methods\",\n      \"pmids\": [\"36649378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREBH normalizes diabetic dyslipidemia via an APOE-dependent mechanism: active CREBH enriches APOE on TRL remnants and depletes APOC3, promoting hepatic clearance of remnant lipoproteins. This mechanism is independent of LPL (confirmed in LPL-deficient mice) but requires APOE (fails in Apoe-/- mice).\",\n      \"method\": \"LPL-deficient and Apoe-/- mouse genetic models with CREBH adenoviral expression, lipoprotein particle profiling, apolipoprotein composition analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent genetic epistasis models (LPL KO and APOE KO) to dissect mechanism; rigorous lipoprotein characterization\",\n      \"pmids\": [\"34491909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CREBH promotes SIRT3 expression, which deacetylates MnSOD to reduce mitochondrial oxidative stress and inhibits NLRP3 inflammasome activation. CREBH overexpression alleviates mitochondrial oxidative stress in NASH; SIRT3 suppression abolishes this protective effect; CREBH KO mice show elevated oxidative stress and NASH susceptibility.\",\n      \"method\": \"Co-IP (SIRT3–CPT2, SIRT3–ACADL interaction), acetylation assay of MnSOD, NLRP3 inflammasome activation measurement, CREBH KO and OE mouse/cell models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and acetylation assay link CREBH→SIRT3→MnSOD deacetylation; single lab, needs replication\",\n      \"pmids\": [\"35926687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion under energy demands. Activated CREBH, cooperating with PPARα, drives expression of UPRmt regulators ATF5 and ATF4. CREBH deficiency causes accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and shifts energy metabolism from fatty acid oxidation toward carbohydrate oxidation.\",\n      \"method\": \"MAM fractionation, CREBH KO mouse phenotyping, mitochondrial membrane potential assay, mitochondrial unfolded protein detection, Co-IP (CREBH–PPARα), gene expression analysis, metabolic flux measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — subcellular fractionation showing MAM localization plus genetic KO phenotype plus Co-IP plus mechanistic ATF5/ATF4 target gene analysis; multiple orthogonal methods\",\n      \"pmids\": [\"39589874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TNFα induces CREBH expression via NF-κB signaling in osteoblasts; active CREBH increases Smurf1 expression leading to ubiquitin-dependent degradation of Smad1, thereby inhibiting BMP2-induced osteoblast differentiation. CREBH knockdown attenuates TNFα-mediated Smad1 degradation and rescues osteoblast differentiation.\",\n      \"method\": \"Co-IP (Smad1–Smurf1), siRNA knockdown, adenoviral CREBH overexpression, ALP/osteocalcin assays, ectopic bone formation in vivo\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and loss-of-function establish CREBH→Smurf1→Smad1 degradation pathway; single lab\",\n      \"pmids\": [\"25873397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hepatic CREBH is a positive transcriptional regulator of CYP2B family genes (e.g., CYP2B10); CREBH ectopic expression increases CYP2B10 promoter activity, and CREBH-deficient mice show severely impaired CYP2B induction and resistance to sulpyrine-induced fatal shock. Reintroduction of CYP2B into CREBH-deficient liver restores sulpyrine susceptibility.\",\n      \"method\": \"Promoter-luciferase assay, CREBH KO mouse, in vivo knockdown (siRNA), adenoviral CYP2B rescue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus genetic rescue in vivo; single lab, phenotypic but mechanistic pathway clearly defined\",\n      \"pmids\": [\"23409047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CREB-H induces expression of Cgref1 (a secreted hepatokine) via direct transcriptional regulation. Secreted Cgref1 suppresses insulin signaling and glucose uptake in epididymal white adipose tissue, creating eWAT insulin resistance that in turn promotes hepatic de novo lipogenesis.\",\n      \"method\": \"Microarray of Creb3l3-/- mice, Cgref1 KO mice, transcriptomic/metabolomic/lipidomic analysis, gain/loss-of-function in hepatocytes, insulin signaling assay in eWAT\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model combined with multi-omics; single lab; specific CREBH-binding to Cgref1 promoter not directly verified by ChIP in abstract\",\n      \"pmids\": [\"40303310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish creb3l3 double mutants (lacking both orthologs), key creb3l3 target genes apoC2 and apoA4 are downregulated in intestines; mutants show impaired lipoprotein turnover (not reduced total lipoprotein production) and increased enterocyte lipid droplet size and number, establishing creb3l3 as a regulator of postprandial intestinal lipid flux balancing storage vs. secretion.\",\n      \"method\": \"Zebrafish genetic KO (CRISPR), lipoprotein reporter lines, histological lipid droplet analysis, gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vertebrate model with defined lipoprotein and gene expression readouts; ortholog study\",\n      \"pmids\": [\"40449732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREBH promotes autophagic flux by transcriptionally repressing Coronin 1a (Coro1a), a gene that inhibits autophagosome-lysosome fusion. Overexpression of Coro1a in hepatocytes blocks autophagic flux; CREBH deficiency aggravates dysfunctional autophagy and liver injury in NASH.\",\n      \"method\": \"Autophagic flux assay (LC3-II, p62), lysosomal marker (LAMP1) imaging, CREBH KO in NASH mouse models, Coro1a promoter reporter, adenoviral Coro1a overexpression\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional target identification with reporter plus KO phenotype plus functional Coro1a rescue; single lab\",\n      \"pmids\": [\"37837948\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CREBH (CREB3L3) is an ER-tethered, liver- and intestine-enriched bZIP transcription factor that is activated by regulated intramembrane proteolysis (RIP) at the Golgi by S1P/S2P proteases, releasing an N-terminal fragment that translocates to the nucleus; ER retention is mediated by a cytoplasmic ERM motif (not lumenal BiP binding as in ATF6), forward ER-to-Golgi transport is gated by GSK-3β phosphorylation of a serine-rich P-motif, and the active nuclear fragment is rapidly degraded via K48-linked polyubiquitination by SCF(β-TrCP/Fbw1a) or HRD1 ERAD-mediated K294 ubiquitination, with the balance between ERAD and productive cleavage controlled by cellular stress load; PCAF-mediated acetylation at K294 and SIRT1-mediated deacetylation modulate CREBH transcriptional potency and its interaction with PPARα; the active form drives hepatic acute-phase response (CRP, SAP), gluconeogenesis (PEPCK, G6Pase), fatty acid oxidation, ketogenesis, apolipoprotein (ApoA-I, ApoA-IV, ApoA-V, ApoC-II) and FGF21 expression—the latter through a CREBH–PPARα heterodimeric complex binding composite CRE–PPRE elements—while the C-terminal cleavage fragment is secreted as a hepatokine (CREBH-C) that disrupts the ANGPTL3–ANGPTL8 complex to activate lipoprotein lipase and promote triglyceride clearance; CREBH also regulates hepatic autophagy, mitochondrial unfolded protein response, VLDL assembly via apoB, and competes with SREBPs for ER-to-Golgi transport, collectively maintaining systemic lipid, glucose, and energy homeostasis across fasting-feeding and circadian cycles.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CREB3L3 (CREBH) is a liver- and intestine-enriched, ER-tethered bZIP transcription factor that functions as a master regulator of systemic lipid, glucose, and energy homeostasis across fasting-feeding and circadian cycles [#0, #7, #19, #22]. Like other CREB3-family factors it is synthesized as a membrane-anchored precursor and activated by regulated intramembrane proteolysis: ER stress or stimulation triggers cleavage by Golgi site-1 and site-2 proteases, liberating an N-terminal fragment that enters the nucleus and binds CRE, box-B, and ATF6 elements to drive transcription [#0, #1, #2]. Multiple layers control this activation. ER retention is set by a cytoplasmic ERM determinant rather than lumenal BiP binding as in ATF6, and N-linked glycosylation of three lumenal sites is required for efficient proteolytic activation [#3, #5, #6]. GSK-3\\u03b2/CKII phosphorylation of a serine-rich P-motif both restrains ER-to-Golgi transport by gating COPII association and, in the nuclear product, primes the SDSGIS phosphodegron for SCF(\\u03b2-TrCP/Fbw1a)-mediated K48 polyubiquitination and proteasomal turnover, while the Sel1L\\u2013HRD1 ERAD complex degrades the precursor and active fragment via K294 ubiquitination\\u2014coupling transport, stability, and circadian timing through BMAL1 [#16, #17, #18, #25, #26, #27, #31]. Transcriptional potency is further tuned by PCAF-mediated K294 acetylation and SIRT1 deacetylation, which licenses a CREBH\\u2013PPAR\\u03b1 heterodimeric complex that binds composite CRE\\u2013PPRE elements [#12, #14]. Through this axis CREBH drives the hepatic acute-phase response (CRP, SAP), gluconeogenesis (PEPCK, G6Pase) and glycogenolysis, fatty acid oxidation and ketogenesis, autophagy and lysosomal biogenesis, the mitochondrial unfolded protein response, and an extensive lipoprotein program including ApoA-IV, ApoA-I, FGF21, and intestinal cholesterol handling via Npc1l1 [#2, #7, #12, #13, #19, #20, #21, #22, #28, #35]. Its secreted C-terminal hepatokine fragment disrupts the ANGPTL3\\u2013ANGPTL8 complex to activate lipoprotein lipase and clear triglycerides, and active CREBH additionally normalizes dyslipidemia through an APOE-dependent remodeling of remnant lipoproteins [#32, #33]. Full-length ER-resident CREBH also restrains lipogenesis by sequestering SREBP in the SREBP\\u2013INSIG1 complex [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established CREBH as a liver-specific, ER-membrane-anchored bZIP factor whose activation depends on release from the membrane, defining the basic regulatory logic of a latent transcription factor.\",\n      \"evidence\": \"GFP imaging, EMSA, GAL4 transactivation and luciferase reporters with transmembrane-domain deletion\",\n      \"pmids\": [\"11353085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the protease or the physiological activating stimulus\", \"DNA-target gene program in vivo not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the activating proteolysis as S1P/S2P cleavage at the Golgi upon ER stress and linked CREBH to the hepatic acute-phase response, converting a localization observation into a defined signaling pathway.\",\n      \"evidence\": \"In vivo cleavage assay, siRNA knockdown, SAP/CRP promoter reporters, LPS/cytokine challenge in mice\",\n      \"pmids\": [\"16469704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How proinflammatory signals are transduced to the cleavage machinery not resolved\", \"Did not address ER-retention determinant\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed CREBH partitions between ERAD-mediated degradation and the productive cleavage pathway, establishing a stress-tuned switch governing how much active factor is produced.\",\n      \"evidence\": \"Subcellular fractionation, proteasome inhibition, glycosylation analysis, ERM-deletion mutagenesis\",\n      \"pmids\": [\"17875199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating basal ERAD not identified at this stage\", \"Cellular signals biasing the switch undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the distinct ER-retention mechanism (cytoplasmic ERM, not lumenal BiP) and a glycosylation requirement for activation, separating CREBH mechanistically from ATF6.\",\n      \"evidence\": \"Domain swap/deletion mutagenesis, BiP co-IP, glycosylation-site mutants with reporter readout\",\n      \"pmids\": [\"19883396\", \"20356926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The trafficking machinery reading the ERM not identified\", \"Why glycosylation is required for cleavage mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected CREBH to hepatic glucose output via direct binding of gluconeogenic promoters and a PPAR\\u03b1-driven feed-forward induction loop, placing it in fasting metabolic control.\",\n      \"evidence\": \"ChIP, EMSA, promoter reporters, adenoviral/siRNA manipulation and blood-glucose phenotyping in mice; PPAR\\u03b1 PPRE in the CREBH promoter\",\n      \"pmids\": [\"20374965\", \"20006574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether glucose effect is fully cell-autonomous in hepatocytes vs systemic not separated\", \"Coactivator requirements only partially defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified upstream inputs and a repressor controlling CREBH activity, showing endocannabinoid/CB1R\\u2013JNK signaling induces CREBH and SMILE competes with PGC-1\\u03b1 to dampen it.\",\n      \"evidence\": \"ChIP, promoter mutagenesis, co-IP/GST pulldown, glucose-production assays in hepatocytes\",\n      \"pmids\": [\"21693703\", \"21994947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance of activators vs SMILE repression in vivo unclear\", \"CB1R-to-CREBH signaling steps between JNK and promoter incompletely mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved CREBH\\u2013PPAR\\u03b1 as a binary complex binding composite CRE\\u2013PPRE elements and identified direct apolipoprotein targets, establishing the molecular basis of its lipid/FGF21 transcriptional output.\",\n      \"evidence\": \"Reciprocal co-IP, ChIP at the FGF21 promoter, EMSA at Apoa4 sites, gain/loss-of-function in mice\",\n      \"pmids\": [\"24424044\", \"24598141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural architecture of the CREBH\\u2013PPAR\\u03b1 complex unknown\", \"Full genome-wide target set not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined post-translational tuning of CREBH: PCAF/SIRT1 acetylation at K294 licenses PPAR\\u03b1 partnership, while GSK-3/CKII phosphorylation of the P-motif and an SDSGIS phosphodegron target the nuclear form for SCF(\\u03b2-TrCP/Fbw1a) degradation.\",\n      \"evidence\": \"Site-directed mutagenesis, co-IP, in vitro kinase assays, ubiquitination assays, in vivo K294R mutant phenotyping\",\n      \"pmids\": [\"26438600\", \"26108621\", \"27029215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How acetylation and phosphorylation are coordinated on the same molecule unresolved\", \"Kinase/acetyltransferase recruitment mechanism not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Integrated CREBH activation into circadian physiology, showing BMAL1/GSK3\\u03b2-gated COPII-dependent transport rhythmically controls cleavage, and demonstrated genetically separable contributions to fatty acid oxidation/ketogenesis.\",\n      \"evidence\": \"Circadian cleavage profiling, BMAL1 KO, GSK3\\u03b2 inhibition, COPII co-IP; Creb3l3/Ppara double-KO epistasis\",\n      \"pmids\": [\"27507854\", \"27982131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PPAR\\u03b1-independent target genes for oxidation not fully enumerated\", \"Mechanism linking GSK3\\u03b2 phosphorylation to COPII selection incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended CREBH to lipoprotein and cholesterol homeostasis in liver and intestine, directly activating Apoa1 and Fsp27\\u03b2 and repressing intestinal Npc1l1.\",\n      \"evidence\": \"Reporter assays, reciprocal tissue-specific transgenic and KO mouse models with lipid/atherosclerosis phenotyping\",\n      \"pmids\": [\"27417587\", \"25125366\", \"27818935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific cofactors distinguishing hepatic vs intestinal programs unclear\", \"Fsp27\\u03b2 (lipid storage) vs apolipoprotein (clearance) balance not reconciled\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped additional upstream control (TLR/MyD88\\u2013TRAF6 K63-ubiquitination promoting cleavage) and expanded function to circadian glucose homeostasis, fibrogenic TGF-\\u03b22, and CYP2B drug metabolism.\",\n      \"evidence\": \"Co-IP, linkage-specific ubiquitination assays, ChIP, KO mouse phenotyping across inflammatory, glucose, fibrosis and xenobiotic readouts\",\n      \"pmids\": [\"27637329\", \"28461393\", \"28621467\", \"23409047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How K63 ubiquitination mechanistically facilitates cleavage unresolved\", \"Interplay between inflammatory and metabolic activation inputs not integrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Unified P-motif phosphorylation as a dual-purpose control, gating ER-to-Golgi transport of the precursor and the stability of the nuclear product, coupling activation amplitude to nuclear lifetime.\",\n      \"evidence\": \"GSK-3 inhibition, serine-to-alanine mutagenesis, phosphospecific antibody, fractionation and transcription assays\",\n      \"pmids\": [\"28381424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial separation of the two P-motif functions not fully resolved\", \"Phosphatase counter-regulation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the Sel1L\\u2013HRD1 ERAD complex as the dominant E3 system controlling CREBH abundance via K294 K48-ubiquitination, with FGF21 as a key output, defining a stress/feeding-tuned protein-stability rheostat.\",\n      \"evidence\": \"Liver-specific Sel1L and HRD1 KO mice, K294 ubiquitin site-mapping, co-IP, stability assays, FGF21 measurement (two groups)\",\n      \"pmids\": [\"30389665\", \"30389664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between K294 ubiquitination and K294 acetylation on the same residue not mechanistically reconciled\", \"How ERAD selects CREBH among substrates unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established CREBH as a transcriptional driver of hepatic autophagy and lysosomal biogenesis acting with PPAR\\u03b1/PGC-1\\u03b1, broadening its catabolic role beyond gene-by-gene metabolic targets.\",\n      \"evidence\": \"KO mouse autophagy-flux phenotyping, co-IP of the CREBH\\u2013PPAR\\u03b1\\u2013PGC-1\\u03b1 complex, ChIP on autophagy gene promoters\",\n      \"pmids\": [\"30912978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect regulation of individual ATG genes not fully separated\", \"Coordination with mTOR/TFEB autophagy control unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a non-transcriptional ER function: full-length CREBH retains SREBP via the SREBP\\u2013INSIG1 complex, positioning CREBH as a brake on lipogenesis in addition to its nuclear catabolic program.\",\n      \"evidence\": \"Co-IP, SREBP nuclear/cytoplasmic fractionation, KO and tissue-specific KO lipid phenotyping; glycosylation modulation of activation\",\n      \"pmids\": [\"33246135\", \"32996649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction data awaits independent replication\", \"Whether precursor sequestration competes quantitatively with cleavage in vivo unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated mechanistic specificity in triglyceride clearance: CREBH normalizes diabetic dyslipidemia through APOE-dependent remnant clearance (LPL-independent), and circadian HRD1/Sel1L turnover of CREBH shapes diurnal lipid/glucose profiles.\",\n      \"evidence\": \"LPL-deficient and Apoe-/- genetic epistasis with CREBH adenovirus; HRD1/CREBH KO circadian metabolite profiling with rescue\",\n      \"pmids\": [\"34491909\", \"33592335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CREBH alters APOE/APOC3 ratios on particles mechanistically unclear\", \"Reconciliation of LPL-dependent (hepatokine) and LPL-independent (APOE) clearance routes incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the secreted C-terminal hepatokine CREBH-C as an endocrine effector, showing CaMKII-dependent secretion and disruption of the ANGPTL3\\u2013ANGPTL8 complex to activate LPL, giving the C-terminal fragment its own signaling function.\",\n      \"evidence\": \"Conditioned-media/plasma detection, CaMKII inhibition/kinase assay, ANGPTL3\\u2013ANGPTL8 co-IP, in vivo LPL activity and CREBH-C administration\",\n      \"pmids\": [\"36649378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor or surface engagement of CREBH-C at peripheral tissues unknown\", \"Relative contribution of CREBH-C vs nuclear CREBH to lipid lowering not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked CREBH to mitochondrial proteostasis and contact-site biology, showing it expands MAMs and, with PPAR\\u03b1, drives the UPRmt regulators ATF5/ATF4 to sustain fatty acid oxidation.\",\n      \"evidence\": \"MAM fractionation, KO mouse phenotyping, membrane-potential and unfolded-protein assays, co-IP, metabolic flux\",\n      \"pmids\": [\"39589874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CREBH promotes MAM expansion not defined\", \"Direct ChIP evidence at ATF5/ATF4 loci not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the inter-organ output of CREBH, identifying secreted hepatokine Cgref1 as a mediator of adipose insulin resistance and confirming conserved intestinal lipid-flux control in zebrafish.\",\n      \"evidence\": \"Creb3l3-/- multi-omics and Cgref1 KO mice; zebrafish creb3l3 double mutants with lipoprotein reporters and lipid-droplet analysis\",\n      \"pmids\": [\"40303310\", \"40449732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ChIP confirmation of CREBH binding at the Cgref1 promoter lacking\", \"Whether intestinal mechanism in fish fully translates to mammalian enterocytes untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing fates of CREBH\\u2014ERAD degradation, productive RIP cleavage, SREBP sequestration, and C-terminal hepatokine secretion\\u2014are quantitatively coordinated by a single stress/feeding/circadian input remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No integrated model partitioning precursor flux among ERAD, cleavage, and SREBP retention\", \"Structural basis of CREBH\\u2013PPAR\\u03b1 complex and its acetylation-dependent assembly unknown\", \"Receptors for secreted CREBH-C and Cgref1 unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 7, 12, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 13, 24]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [30, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3, 5, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [35]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 19, 20, 21, 22, 33]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 12, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 3, 35]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16, 17, 26, 27, 31]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [28, 40]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [18, 22, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 23]}\n    ],\n    \"complexes\": [\n      \"CREBH\\u2013PPAR\\u03b1 transcriptional complex\",\n      \"SCF(\\u03b2-TrCP/Fbw1a) E3 ligase complex (substrate)\",\n      \"Sel1L\\u2013HRD1 ERAD complex (substrate)\",\n      \"SREBP\\u2013INSIG1 complex (associated)\"\n    ],\n    \"partners\": [\n      \"PPARA\",\n      \"SREBF (SREBP)\",\n      \"INSIG1\",\n      \"BTRC (\\u03b2-TrCP/Fbw1a)\",\n      \"HRD1 (SYVN1)\",\n      \"SEL1L\",\n      \"TRAF6\",\n      \"CREBZF (SMILE)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}