{"gene":"ATF5","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2016,"finding":"ATF5 mediates the mammalian mitochondrial unfolded protein response (UPRmt) by organelle partitioning: normally sequestered in mitochondria, ATF5 accumulates in the cytosol and traffics to the nucleus during mitochondrial stress to activate UPRmt transcriptional targets. ATF5 expression rescues UPRmt signaling in atfs-1-deficient C. elegans via the same UPRmt promoter element, demonstrating functional conservation.","method":"Cell fractionation, C. elegans genetic rescue, mammalian cell knockdown with mitochondrial stress assays, transcriptional reporter assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, genetic rescue, knockdown + phenotypic readout) in a single high-impact study, replicated conceptually in multiple downstream studies","pmids":["27426517"],"is_preprint":false},{"year":2008,"finding":"ATF5 protein expression is translationally upregulated in response to diverse stresses (ER stress, arsenite, proteasome inhibition) via eIF2α phosphorylation. The ATF5 5'-UTRα contains two uORFs analogous to ATF4: uORF1 is positive-acting allowing reinitiation, while uORF2 is inhibitory under normal conditions; eIF2 phosphorylation during stress permits ribosomes to bypass uORF2 and translate the ATF5 coding region. ATF4 also contributes to basal ATF5 mRNA transcription.","method":"Polyribosome fractionation, luciferase reporter mutagenesis of 5'-UTR uORFs, ATF4 knockout MEF analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted translational mechanism with mutational analysis, replicated and consistent with parallel study (PMID:18055463)","pmids":["18195013"],"is_preprint":false},{"year":2007,"finding":"ATF5 mRNA translation is regulated by alternative 5'-UTRs (5'-UTRα and 5'-UTRβ): 5'-UTRα represses translation under normal conditions, and this repression is relieved by amino acid limitation or arsenite via eIF2α phosphorylation. Mutation of uAUG2 in uORF2 abolishes stress-induced translational upregulation.","method":"Luciferase reporter assay with 5'-UTR mutants, eIF2α phosphorylation analysis, heme-regulated inhibitor kinase overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reporter system with mutagenesis, consistent with PMID:18195013","pmids":["18055463"],"is_preprint":false},{"year":2013,"finding":"CHOP directly induces ATF5 transcription in response to proteasome inhibition; ATF5 in turn activates pro-apoptotic targets including NOXA, creating a feedforward loop. Both ATF4 and CHOP directly transcriptionally activate ATF5. ATF5 knockdown increases cell survival during proteasome inhibition, indicating a pro-apoptotic function.","method":"Promoter reporter assays, siRNA knockdown, transcriptome analysis, cell viability assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (transcriptomics, reporter assays, knockdown + survival readout) in single study","pmids":["23761072"],"is_preprint":false},{"year":2010,"finding":"In malignant glioma, RAS-MAPK or PI3K signaling activates CREB3L2, which directly activates ATF5 transcription; ATF5 in turn promotes survival by stimulating transcription of MCL1, an anti-apoptotic BCL-2 family member.","method":"Genome-wide RNAi screen, chromatin immunoprecipitation, reporter assays, siRNA knockdown, mouse xenograft models","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — genome-wide unbiased screen with ChIP and in vivo validation, multiple orthogonal methods","pmids":["20495567"],"is_preprint":false},{"year":2011,"finding":"BCR-ABL suppresses autophagy through the PI3K/AKT/FOXO4 pathway, which transcriptionally upregulates ATF5; ATF5 then stimulates transcription of mTOR, a master negative regulator of autophagy. Imatinib-induced autophagy results from inhibition of this BCR-ABL/PI3K/AKT/FOXO4/ATF5/mTOR pathway.","method":"Reporter assays, ChIP, siRNA knockdown, pharmacological inhibition, BCR-ABL transformed cell lines","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including ChIP, reporter assays, and epistasis experiments","pmids":["21715304"],"is_preprint":false},{"year":2003,"finding":"ATF5 promotes neuroprogenitor cell expansion and blocks differentiation into neurons; NGF downregulates ATF5 protein and transcripts, and exogenous ATF5 suppresses NGF-promoted neurite outgrowth requiring CRE site repression. Dominant-negative ATF5 or siRNA targeting ATF5 accelerates neurogenesis.","method":"PC12 cell overexpression/knockdown, dominant-negative ATF5, siRNA, clonal neurosphere cultures, NGF treatment","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple loss- and gain-of-function approaches with defined cellular phenotype","pmids":["12805299"],"is_preprint":false},{"year":2011,"finding":"BCL-2 is a direct downstream transcriptional target of ATF5: ATF5 binds to an ATF5-specific regulatory element downstream of the BCL-2 P2 promoter to stimulate BCL-2 expression in C6 glioma and MCF-7 breast cancer cells but not in non-transformed cells, explaining cell-type-dependent survival function.","method":"Promoter reporter assays, electrophoretic mobility shift assay (EMSA), ChIP, siRNA knockdown, dominant-negative ATF5","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding demonstrated by EMSA and ChIP, functional validation by knockdown and rescue","pmids":["21212266"],"is_preprint":false},{"year":2011,"finding":"ATF5 interacts with the transcriptional coactivator p300, which acetylates ATF5 at lysine-29; this acetylation enhances ATF5-p300 interaction and binding to the ATF5 response element (ARE) in the Egr-1 promoter. The ATF5/p300 complex then acetylates histone H3 at K14 at both ARE and SRE regions, facilitating ERK-phosphorylated Elk-1 binding and activating Egr-1 transcription.","method":"Co-IP, in vitro acetylation assays, ChIP, mutagenesis of acetylation sites, reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro acetylation assay, ChIP, mutagenesis, co-IP — multiple orthogonal methods","pmids":["21791614"],"is_preprint":false},{"year":2011,"finding":"HSP70 interacts with the N-terminal activation domain of ATF5 (which is proline-rich) in an ATP-driven, ATPase-dependent manner. HSP70 binding stabilizes ATF5 protein against proteasome- and caspase-dependent degradation; HSP70 depletion accelerates ATF5 degradation and reduces downstream BCL-2 and Egr-1 expression.","method":"Co-IP, overexpression/knockdown, proteasome inhibitor experiments, ATPase mutant HSP70","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with mechanistic domain mapping, ATPase mutant validation, functional consequences","pmids":["21521685"],"is_preprint":false},{"year":2012,"finding":"Nucleophosmin (NPM1/B23) was identified by tandem affinity purification/mass spectrometry as an ATF5-interacting protein; NPM1 binds ATF5 via its C-terminal region (nucleolar localization domain) interacting with the ATF5 bZIP domain. NPM1 binding promotes ATF5 polyubiquitination and degradation via proteasome- and caspase-dependent pathways, displacing HSP70 from ATF5. NPM1-c mutant lacking nucleolar localization fails to degrade ATF5.","method":"Tandem affinity purification, mass spectrometry, co-IP, ubiquitination assays, NPM1-c mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — unbiased TAP-MS identification with mechanistic follow-up including mutant analysis and ubiquitination assays","pmids":["22528486"],"is_preprint":false},{"year":2015,"finding":"ATF5 forms a 9-fold symmetrical ring structure at the proximal end of the mother centriole in the inner layer of the pericentriolar material (PCM). ATF5 interacts with polyglutamylated tubulin on the mother centriole and with pericentrin (PCNT) in the PCM, controlling centriole-PCM interaction in a cell-cycle- and centriole-age-dependent manner. ATF5 depletion blocks PCM accumulation, causes centriole fragmentation, and leads to multipolar mitotic spindles and genomic instability.","method":"Super-resolution microscopy (structured illumination), co-IP, siRNA knockdown, cell cycle synchronization, immunofluorescence","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — structural characterization by super-resolution microscopy plus co-IP and loss-of-function with multiple phenotypic readouts","pmids":["26213385"],"is_preprint":false},{"year":2018,"finding":"ATF5 is SUMO2/3-modified at a conserved consensus site; SUMOylation is elevated in G1 phase and diminished in G2/M phase. SUMOylation disrupts ATF5 interaction with centrosomal proteins and dislodges ATF5 from the centrosome at end of M phase. Blocking ATF5 SUMOylation deregulates the centrosome cycle, prevents ATF5 translocation from the centrosome, and causes genomic instability and G2/M arrest.","method":"SUMO modification assay, co-IP, cell cycle synchronization, mutagenesis of SUMO consensus site, centrosome localization by immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical PTM identification with site mutagenesis and functional consequence on centrosome cycle","pmids":["29326161"],"is_preprint":false},{"year":2008,"finding":"ATF5 protein is degraded via the ubiquitin-proteasome pathway through N-terminal ubiquitinylation at the free amino group of the N-terminal methionine. Cisplatin stabilizes ATF5 by promoting nucleus-to-cytoplasm translocation of E2 ubiquitin-conjugating enzyme Cdc34, reducing the interaction between ATF5 and Cdc34.","method":"Ubiquitination assays, N-terminal tagging experiments, Cdc34 localization analysis, co-IP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic dissection of ubiquitination site with functional mutants and identification of E2 enzyme","pmids":["18458088"],"is_preprint":false},{"year":2012,"finding":"In glioma, the endoplasmic reticulum stress transducer BBF2H7 directly activates ATF5 transcription; ATF5 in turn activates MCL1 transcription to suppress ER stress-induced apoptosis in chondrocytes. Loss of BBF2H7 leads to loss of ATF5 and MCL1, and increased apoptosis in proliferating chondrocytes.","method":"Bbf2h7 knockout mice, reporter assays, ChIP, immunostaining, TUNEL","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout mouse with mechanistic pathway dissection by ChIP and reporter assays","pmids":["22936798"],"is_preprint":false},{"year":2019,"finding":"Dominant-negative ATF5 (DN-ATF5) kills tumor cells by associating with and blocking the transcriptional activities of CEBPB and CEBPD (not exclusively ATF5 itself), as revealed by unbiased pull-down/mass spectrometry. CEBPB or CEBPD knockdown causes apoptosis of multiple cancer cell lines but not normal astrocytes. DN-ATF5 interferes with CEBPB/CEBPD homodimer and heterodimer formation.","method":"Pull-down with mass spectrometry, co-IP, siRNA knockdown, transcriptional reporter assays, cell viability","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 1-2 — unbiased MS identification of interactors with functional validation by knockdown and reporter assays","pmids":["31676720"],"is_preprint":false},{"year":2013,"finding":"ATF5 5'-UTRα reduces ATF5 mRNA stability by making it a target of nonsense-mediated mRNA decay (NMD): uORF2 translation terminates 125 nt upstream of an exon junction, fulfilling NMD criteria. Knockdown of NMD factors Upf1/Upf2 stabilizes ATF5 mRNA in a uAUG2-dependent manner. Stress-induced eIF2α phosphorylation bypasses uORF2 and stabilizes ATF5 mRNA.","method":"Upf1/Upf2 siRNA knockdown, uAUG2 mutagenesis, mRNA stability assays, eIF2α phosphorylation analysis","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 — mechanistic reconstitution with mutagenesis and NMD factor knockdown experiments","pmids":["23876217"],"is_preprint":false},{"year":2012,"finding":"ATF5 is required for terminal differentiation and survival of olfactory sensory neurons (OSNs): Atf5 knockout mice show massive reduction of mature OSNs due to a differentiation defect and induction of apoptosis. Atf5 is expressed in immature and all mature OSNs, and ectopic Atf5 expression in neural progenitor cells induces OSN-specific gene expression.","method":"Atf5 knockout mice, immunostaining with OSN markers, expression profiling, ectopic gene expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout mouse with defined cellular phenotype and marker analysis","pmids":["23090999"],"is_preprint":false},{"year":2017,"finding":"PDX1 directly binds the Atf5 promoter (by ChIP-seq) and regulates ATF5 expression in β-cells. ATF5 is positioned downstream of and parallel to ATF4 in regulating 4EBP1, a mTOR pathway component that inhibits protein translation. ATF5 deficiency attenuates stress suppression of global translation, enhancing β-cell susceptibility to stress-induced apoptosis.","method":"ChIP-seq, siRNA knockdown, chromatin occupancy, loss-of-function in β-cell stress models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq for direct binding plus epistasis experiments and loss-of-function phenotype","pmids":["28115692"],"is_preprint":false},{"year":2019,"finding":"Pharmacological UPRmt induction is cardioprotective in an ATF5-dependent manner: in vivo UPRmt inducers protect against cardiac ischemia-reperfusion injury in wild-type but not global Atf5-/- mice. RNA-Seq revealed an ATF5-dependent gene set upregulated by UPRmt induction.","method":"Atf5 global knockout mice, ex vivo and in vivo ischemia-reperfusion injury model, RNA-Seq, qPCR/Western blot","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout mouse with in vivo functional phenotype and transcriptomics","pmids":["31274354"],"is_preprint":false},{"year":2014,"finding":"NLK (Nemo-like kinase) interacts with ATF5 and inhibits its proteasome-dependent degradation in a kinase-independent manner. TAK1, acting upstream of NLK downstream of IL-1β, similarly stabilizes ATF5. NLK and ATF5 cooperate to activate C/EBP, and NLK cannot activate C/EBP upon ATF5 knockdown.","method":"Co-IP, NLK/ATF5 overexpression and knockdown, proteasome inhibition, luciferase reporter assay, NLK kinase-dead mutant","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — co-IP with kinase-dead mutant, epistasis by knockdown, multiple readouts","pmids":["25512613"],"is_preprint":false},{"year":2009,"finding":"ATF5 protein is degraded via the ubiquitin-proteasome pathway; cadmium stabilizes ATF5 protein by interfering with a post-ubiquitination step of proteasomal degradation without reducing ubiquitination of ATF5. The N-terminal region contains a nuclear export signal but is not the ubiquitination site.","method":"Ubiquitination assays, proteasome inhibitor comparison, cadmium treatment, N-terminal deletion mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical dissection of degradation mechanism, single lab","pmids":["19285020"],"is_preprint":false},{"year":2013,"finding":"ATF5 overexpression in adult neurons reduces ER stress-induced apoptosis; ATF5 levels increase in hippocampal neurons upon ER stress (tunicamycin injection or kainate-induced status epilepticus). ATF5 induction occurs preferentially in neuronal fields resistant to apoptosis, suggesting a neuroprotective role.","method":"ATF5 overexpression/siRNA in primary neuronal cultures, in vivo status epilepticus model, in situ hybridization, immunohistochemistry","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function in neuronal cultures with apoptosis readout, supported by in vivo model","pmids":["23518711"],"is_preprint":false},{"year":2008,"finding":"ATF5 is a liver-enriched transcription factor that cooperates with constitutive androstane receptor (CAR) to transactivate CYP2B6; re-expression of ATF5 in HepG2 cells by adenoviral transduction markedly upregulates CYP2B6 mRNA. ATF5 and CYP2B6 are co-induced under ER stress conditions.","method":"Adenoviral transduction, qRT-PCR, cotransfection with CAR, ER stress induction","journal":"Drug metabolism and disposition: the biological fate of chemicals","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, overexpression approach, moderate mechanistic follow-up","pmids":["18332083"],"is_preprint":false},{"year":2005,"finding":"ATF5 activates asparagine synthetase (ASNS) promoter transcription via the nutrient-sensing response unit (NSRU) but not via CRE-containing elements. CHOP impairs ATF5-mediated or ATF4-mediated transcriptional activation of the ASNS promoter following amino acid deprivation.","method":"Promoter reporter assays (transient transfection), overexpression of ATF5 and CHOP","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay-based mechanism, single lab, no direct binding demonstrated","pmids":["16164412"],"is_preprint":false},{"year":2008,"finding":"ATF5 suppresses the transactivational activity of p53 and p63 as demonstrated by luciferase reporter assays; ATF5 gene transfer restores radioresistance in a radiosensitive clone that lost ATF5 expression.","method":"Luciferase reporter assay for p53/p21, ATF5 gene transfer, microarray, colony assay","journal":"Cell structure and function","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay with functional rescue, single lab, limited mechanistic detail on binding","pmids":["19293535"],"is_preprint":false},{"year":2017,"finding":"Human cytomegalovirus immediate-early protein IE86 physically interacts with and acetylates ATF5, promoting glioma cell survival. IE86 staining positively correlates with ATF5 staining in GBM samples.","method":"Co-IP, acetylation assay, overexpression, in vitro and in vivo tumor growth assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with acetylation assay, single lab","pmids":["28473657"],"is_preprint":false},{"year":2022,"finding":"ATF5 is required for mitochondrial quality control in skeletal muscle: ATF5 KO mice show enlarged, less functional mitochondrial pools with enhanced biogenesis (increased PGC-1α), attenuated mitophagy, reduced antioxidant proteins, increased ROS emission, and blunted UPRmt gene expression response to acute exercise. Acute exercise enriches ATF5 in mitochondrial fractions rather than promoting nuclear translocation.","method":"ATF5 KO mice, subcellular fractionation, mitochondrial oxygen consumption/ROS assays, exercise protocol, Western blot, qPCR","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with multiple organellar function readouts and fractionation experiments","pmids":["36332794"],"is_preprint":false},{"year":2022,"finding":"ATF5 promotes intestinal barrier function and a satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes leptin secretion. This mechanism protects against obesity-associated hyperglycemia that is detrimental to barrier function.","method":"ATF5 conditional and global knockout mice, enteric pathogen challenge, transcriptional analysis, hormone measurements","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout mouse with defined hormonal and metabolic pathway mechanism","pmids":["36516750"],"is_preprint":false},{"year":2023,"finding":"TMEM11 directly interacts with METTL1 and enhances m7G methylation of Atf5 mRNA, increasing ATF5 expression. ATF5 in turn promotes transcription of Inca1 (a CDK inhibitor), suppressing cardiomyocyte proliferation. TMEM11 deletion enhances cardiomyocyte proliferation and cardiac regeneration after injury.","method":"Co-IP, m7G MeRIP-seq, ATF5 overexpression, ChIP, siRNA knockdown, in vivo myocardial injury model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 — epitranscriptomic mechanism identified by MeRIP-seq, co-IP, and in vivo genetic model","pmids":["37286744"],"is_preprint":false},{"year":2012,"finding":"ATF5 reciprocally interacts with Sonic hedgehog (Shh) signaling in cerebellar granule neuron progenitors (CGNPs): Shh promotes ATF5 expression via a post-transcriptional (protein stabilization) mechanism, and ATF5 in turn promotes Shh-stimulated CGNP proliferation and delays differentiation. Dominant-negative ATF5 diminishes Shh-stimulated CGNP proliferation.","method":"Dominant-negative ATF5, constitutive ATF5 expression in CGNPs, Shh treatment, BrdU proliferation assay, protein stability analysis","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with defined cellular phenotype, single lab","pmids":["22095825"],"is_preprint":false},{"year":2010,"finding":"The ATF5 promoter was mapped to the region −105 to +3 relative to the transcription start site. EBF1 transcription factor binds to the ATF5 promoter and regulates ATF5 transcription in an EBF-binding-site-independent manner.","method":"Promoter deletion analysis, luciferase reporter assay, EBF1 binding analysis","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay-based promoter mapping, single lab","pmids":["20423929"],"is_preprint":false},{"year":2013,"finding":"ATF5 protein is stabilized by IL-1β through its N-terminal hydrophobic amino acids, which serve as both a destabilization domain under steady-state conditions and an IL-1β response domain. IL-1β also increases ATF5 translational efficiency via 5'-UTRα and eIF2α phosphorylation. ATF5 negatively regulates IL-1β-induced SAA1 and SAA2 gene expression.","method":"N-terminal deletion/point mutants, protein stability assays, translational efficiency analysis, ATF5 siRNA knockdown, SAA1/SAA2 mRNA measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis of stability domain with functional consequences, single lab","pmids":["24379400"],"is_preprint":false},{"year":2021,"finding":"ELF1 transcription factor binds to and activates the ATF5 gene promoter in glioma; ELF1 silencing inhibits glioma cell growth and migration via ATF5. Luciferase assay and ChIP confirm direct ELF1 binding to the ATF5 promoter.","method":"Luciferase reporter assay, ChIP, siRNA knockdown, bioinformatics","journal":"ACS chemical neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay with functional siRNA knockdown, single lab","pmids":["33720698"],"is_preprint":false},{"year":2019,"finding":"PRMT1 promotes neuroblastoma cell survival through ATF5: PRMT1 depletion decreases ATF5 expression and induces apoptosis, while ATF5 overexpression rescues apoptosis triggered by PRMT1 inhibition. ATF5 acts as a downstream effector of PRMT1-mediated survival signaling.","method":"siRNA/shRNA knockdown, PRMT1 inhibitor treatment, ATF5 overexpression rescue, in vitro and in vivo tumor models","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis by rescue experiment, single lab with both in vitro and in vivo data","pmids":["32415090"],"is_preprint":false},{"year":2019,"finding":"Dominant-negative ATF5 rapidly depletes survivin (BIRC5) in tumor cells at both mRNA and protein levels. Survivin protein depletion is driven partly by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss precedes cell death but survivin overexpression does not rescue DN-ATF5-induced apoptosis, indicating multiple mechanisms.","method":"DN-ATF5 vector delivery, qRT-PCR, proteasome inhibitor rescue, USP9X analysis, overexpression rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple readouts for mechanism, single lab","pmids":["31551409"],"is_preprint":false},{"year":2024,"finding":"METTL14 facilitates m6A modification of ATF5 mRNA, promoting its degradation. ATF5 overexpression reverses METTL14-mediated stemness inhibition in gastric cancer by increasing WDR74 transcription and enhancing β-catenin nuclear translocation. ATF5 directly binds and stimulates the WDR74 promoter as shown by ChIP and luciferase assays.","method":"MeRIP assay, luciferase reporter assay, ChIP, siRNA knockdown, Western blot","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — MeRIP for epitranscriptomic mechanism, ChIP for direct ATF5 target binding, single lab","pmids":["39497511"],"is_preprint":false},{"year":2024,"finding":"In obese female mice, suppressed AMPK activity increases the binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions, promoting replication of heteroplasmic mtDNA and impairing oocyte quality. AMPK activation blocks ATF5-POLG protein recruitment to mutated mtDNA.","method":"AMPK knockout mice, single-oocyte mtDNA sequencing, protein-DNA binding assays, AMPK activator treatment","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic model with direct protein-DNA binding measurements, single lab","pmids":["38499990"],"is_preprint":false},{"year":2019,"finding":"Co-expression of C/EBPγ and ATF5 (but not either alone) increases Vmn2r66 (V2r) promoter reporter activity via the C/EBP:ATF response element (CARE) in Neuro2a cells, suggesting cooperative transcriptional activation in vomeronasal sensory neuron differentiation.","method":"Luciferase reporter assay with CARE site, co-transfection of C/EBPγ and ATF5","journal":"Cell and tissue research","confidence":"Low","confidence_rationale":"Tier 3 — single reporter assay approach, limited functional validation in vivo","pmids":["31309319"],"is_preprint":false},{"year":2021,"finding":"ATF5 is identified as a transcriptional regulator of Idh2 (isocitrate dehydrogenase-2) in skeletal muscle; AAV-mediated ATF5 overexpression reduced muscle fiber size and MyHC-IIB mRNA while increasing MyHC-IIA and Idh2 mRNA, suggesting fiber-type and metabolic gene regulation.","method":"AAV-mediated gene overexpression in mouse tibialis anterior, qRT-PCR, fiber type analysis","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — single overexpression approach without direct binding evidence, single lab","pmids":["34611283"],"is_preprint":false},{"year":2023,"finding":"ASGR1 promotes monocyte-to-macrophage differentiation via upregulation of ATF5 through NF-κB/IKBa phosphorylation; ASGR1 directly interacts with ATF5 as shown by co-IP.","method":"Co-IP, siRNA knockdown/overexpression, Western blot, flow cytometry, in vivo LPS sepsis model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with in vivo genetic model, but mechanistic detail on ATF5 in this pathway is limited","pmids":["36621538"],"is_preprint":false}],"current_model":"ATF5 is a stress-responsive bZIP transcription factor whose activity is regulated at multiple levels: translationally via eIF2α phosphorylation-dependent bypass of inhibitory uORFs in its 5'-UTR, post-translationally via proteasomal degradation (involving N-terminal ubiquitinylation and the E2 enzyme Cdc34, counteracted by HSP70 stabilization and NLK/TAK1-mediated protection), acetylation by p300 (enhancing promoter binding), and SUMOylation (controlling centrosomal localization); it functions as a nuclear transcription factor activating survival genes (MCL1, BCL-2, Egr-1, mTOR, CYP2B6, cholecystokinin) downstream of stress pathways including the mitochondrial UPR, integrated stress response, and oncogenic signaling (RAS/MAPK-CREB3L2, BCR-ABL/PI3K/AKT/FOXO4), and also serves as a structural centrosomal protein forming a 9-fold ring at the mother centriole to scaffold pericentriolar material assembly via interactions with polyglutamylated tubulin and pericentrin."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing ATF5 as a neural progenitor maintenance factor resolved how bZIP transcription factors control the proliferation-to-differentiation switch in neurogenesis.","evidence":"Overexpression, dominant-negative, and siRNA approaches in PC12 cells and neurosphere cultures with NGF treatment","pmids":["12805299"],"confidence":"High","gaps":["Direct transcriptional targets mediating the anti-differentiation effect were not identified","No in vivo loss-of-function model at that time"]},{"year":2007,"claim":"Demonstrating that ATF5 translation is controlled by eIF2α phosphorylation-dependent bypass of inhibitory uORFs in its 5′-UTR established ATF5 as a member of the ISR-regulated translational program alongside ATF4.","evidence":"Luciferase reporters with uORF mutagenesis, eIF2α kinase overexpression, polyribosome fractionation in mammalian cells","pmids":["18055463","18195013"],"confidence":"High","gaps":["Relative contributions of 5′-UTRα versus 5′-UTRβ in different tissues not resolved","Whether additional kinases beyond HRI regulate this switch in vivo"]},{"year":2008,"claim":"Identifying N-terminal ubiquitinylation via the E2 enzyme Cdc34 as the primary ATF5 degradation mechanism explained how ATF5 protein is kept at low steady-state levels and how genotoxic stress (cisplatin) stabilizes ATF5.","evidence":"Ubiquitination assays, N-terminal tagging, Cdc34 localization analysis, co-IP in mammalian cells","pmids":["18458088"],"confidence":"High","gaps":["The E3 ubiquitin ligase responsible was not identified","Whether N-terminal ubiquitinylation applies in all cell types"]},{"year":2010,"claim":"A genome-wide RNAi screen placing ATF5 downstream of RAS-MAPK/CREB3L2 and upstream of MCL1 in glioma established the first oncogenic transcriptional cascade through which ATF5 promotes tumor survival.","evidence":"Genome-wide RNAi screen, ChIP, reporter assays, mouse xenograft models in malignant glioma","pmids":["20495567"],"confidence":"High","gaps":["Whether CREB3L2–ATF5–MCL1 axis operates in non-glioma cancers","Structural basis of ATF5 binding to the MCL1 promoter"]},{"year":2011,"claim":"Multiple studies in 2011 defined a layered post-translational regulatory network: HSP70 stabilizes ATF5 against proteasomal/caspase degradation, p300 acetylates ATF5 at K29 to enhance promoter binding, and ATF5 directly transactivates BCL-2 and Egr-1, clarifying how ATF5 protein activity is fine-tuned and which survival genes it controls.","evidence":"Reciprocal co-IP with domain mapping and ATPase mutants (HSP70); in vitro acetylation, ChIP, and mutagenesis (p300/Egr-1); EMSA and ChIP for BCL-2 promoter binding","pmids":["21521685","21791614","21212266"],"confidence":"High","gaps":["Whether acetylation and HSP70 binding are coordinated or competitive","Identity of deacetylase(s) reversing K29 acetylation"]},{"year":2011,"claim":"Linking BCR-ABL to ATF5-mediated mTOR transcription and autophagy suppression revealed an oncogene–ATF5–mTOR axis controlling autophagy in CML.","evidence":"ChIP, reporter assays, siRNA epistasis, pharmacological inhibition in BCR-ABL-transformed cells","pmids":["21715304"],"confidence":"High","gaps":["Whether ATF5 activates mTOR transcription in non-leukemic contexts","Direct ATF5 binding site on the mTOR promoter not mapped at nucleotide resolution"]},{"year":2012,"claim":"NPM1 was identified as an ATF5 interactor that displaces HSP70 and promotes ATF5 polyubiquitination and degradation, with NPM1-c AML mutant failing to do so—connecting ATF5 stability to nucleolar integrity and AML pathogenesis.","evidence":"TAP-MS, co-IP, ubiquitination assays, NPM1-c mutant analysis","pmids":["22528486"],"confidence":"High","gaps":["Whether NPM1-c-mediated ATF5 stabilization contributes to leukemogenesis in vivo","Stoichiometry of the HSP70–ATF5–NPM1 competition"]},{"year":2012,"claim":"Atf5 knockout mice revealed that ATF5 is essential for terminal differentiation and survival of olfactory sensory neurons, establishing a non-cancer developmental role.","evidence":"Atf5 knockout mice with OSN marker immunostaining and ectopic expression in neural progenitors","pmids":["23090999"],"confidence":"High","gaps":["Direct transcriptional targets of ATF5 driving OSN fate commitment not comprehensively identified","Whether ATF5 cooperates with other bZIP factors in OSN specification"]},{"year":2013,"claim":"Two discoveries added regulatory depth: CHOP directly activates ATF5 transcription creating a feedforward pro-apoptotic loop during proteasome inhibition, and ATF5 mRNA is subject to NMD via uORF2, adding an mRNA stability layer to stress-responsive ATF5 induction.","evidence":"Promoter reporters and siRNA with cell viability readouts (CHOP); Upf1/Upf2 knockdown with uAUG2 mutagenesis and mRNA stability assays (NMD)","pmids":["23761072","23876217"],"confidence":"High","gaps":["Whether NMD regulation of ATF5 contributes to tissue-specific expression patterns","Relative contribution of translational versus NMD regulation under different stresses"]},{"year":2015,"claim":"Super-resolution imaging revealed an entirely unexpected structural role: ATF5 forms a 9-fold symmetrical ring at the proximal end of the mother centriole, scaffolding PCM assembly through interactions with polyglutamylated tubulin and pericentrin, and its loss causes centriole fragmentation and genomic instability.","evidence":"Structured illumination microscopy, co-IP, siRNA knockdown, cell cycle synchronization","pmids":["26213385"],"confidence":"High","gaps":["How a bZIP transcription factor structurally integrates into the centriole wall","Whether centrosomal and nuclear/transcriptional functions are coordinated or independent"]},{"year":2016,"claim":"ATF5 was established as the mammalian mediator of the mitochondrial UPR: normally sequestered in mitochondria, it accumulates in the cytosol and nucleus during mitochondrial stress, functionally rescuing C. elegans atfs-1 loss.","evidence":"Cell fractionation, C. elegans genetic rescue, knockdown with mitochondrial stress assays","pmids":["27426517"],"confidence":"High","gaps":["Import/export mechanism controlling ATF5 mitochondrial sequestration","Whether ATF5 directly senses mitochondrial protein misfolding or responds to secondary signals"]},{"year":2018,"claim":"Demonstrating that SUMO2/3 modification of ATF5 dislodges it from the centrosome at the end of M phase resolved how the centrosomal and nuclear pools of ATF5 are cell-cycle-regulated.","evidence":"SUMO modification assay, SUMO-site mutagenesis, cell cycle synchronization, centrosome immunofluorescence","pmids":["29326161"],"confidence":"High","gaps":["Identity of the SUMO E3 ligase and SENP deconjugase controlling ATF5 SUMOylation","Whether deSUMOylated ATF5 released from centrosomes enters the nucleus to function as a transcription factor"]},{"year":2019,"claim":"Unbiased pull-down/MS revealed that dominant-negative ATF5 kills tumor cells primarily by blocking CEBPB and CEBPD transcriptional activity rather than ATF5 alone, reinterpreting the mechanism of the anti-cancer DN-ATF5 tool.","evidence":"Pull-down with mass spectrometry, co-IP, siRNA knockdown, cell viability assays","pmids":["31676720"],"confidence":"High","gaps":["Whether endogenous ATF5 normally heterodimerizes with CEBPB/CEBPD to regulate shared targets","Therapeutic implications require validation in patient-derived models"]},{"year":2019,"claim":"In vivo ischemia-reperfusion studies in Atf5−/− mice demonstrated that pharmacological UPRmt induction is cardioprotective in an ATF5-dependent manner, extending ATF5's UPRmt role to cardiac protection.","evidence":"Atf5 global knockout mice, ex vivo and in vivo cardiac ischemia-reperfusion models, RNA-Seq","pmids":["31274354"],"confidence":"High","gaps":["ATF5-dependent cardioprotective gene targets not fully characterized","Whether ATF5 operates through the same mitochondria-to-nucleus translocation in cardiomyocytes"]},{"year":2022,"claim":"Atf5 KO mice revealed that ATF5 is required for mitochondrial quality control in skeletal muscle—governing mitophagy, antioxidant defense, and UPRmt gene induction during exercise—extending its organelle maintenance role beyond the heart.","evidence":"ATF5 KO mice, subcellular fractionation, mitochondrial respiration and ROS assays, exercise protocol","pmids":["36332794"],"confidence":"High","gaps":["Whether exercise enrichment of ATF5 in mitochondrial fractions reflects import or membrane association","Tissue-specific versus systemic consequences of ATF5 loss on exercise adaptation"]},{"year":2022,"claim":"Conditional knockout studies showed ATF5 transcriptionally activates cholecystokinin to promote intestinal barrier function and satiety, revealing a gut endocrine role distinct from its stress-response functions.","evidence":"ATF5 conditional and global KO mice, enteric pathogen challenge, hormone measurements","pmids":["36516750"],"confidence":"High","gaps":["Whether ATF5 directly binds the cholecystokinin promoter","How intestinal ATF5 expression is regulated"]},{"year":2023,"claim":"Identification of METTL1-mediated m7G methylation of Atf5 mRNA as a mechanism enhancing ATF5 expression, with ATF5 then activating the CDK inhibitor Inca1 to suppress cardiomyocyte proliferation, connected epitranscriptomics to ATF5-dependent cell cycle control in the heart.","evidence":"m7G MeRIP-seq, co-IP, ChIP, siRNA, in vivo myocardial injury model","pmids":["37286744"],"confidence":"High","gaps":["Whether m7G modification of ATF5 mRNA occurs in non-cardiac contexts","Whether Inca1 is a direct or indirect ATF5 target in other proliferative tissues"]},{"year":null,"claim":"How ATF5's dual roles as a nuclear transcription factor and a structural centrosomal protein are coordinated—including the signals partitioning ATF5 among mitochondria, centrosome, and nucleus, and the E3 ligase(s) controlling its N-terminal ubiquitinylation—remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["E3 ubiquitin ligase for ATF5 not identified","Mechanism of ATF5 import into mitochondria and its release during stress unclear","Whether centrosomal ATF5 pool and transcription factor pool derive from distinct translation or post-translational sorting events"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,5,7,8,17,28,29,36]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,8,29,36]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,8,17]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,27]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[11,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,5,7,8,17,28,29]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1,2,3,19,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,4,7,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,17,30]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,12,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,30]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[11,12,27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,10,13,16]}],"complexes":[],"partners":["HSPA1A","NPM1","EP300","PCNT","NLK","CEBPB","CEBPD","CDC34"],"other_free_text":[]},"mechanistic_narrative":"ATF5 is a stress-responsive bZIP transcription factor that integrates cellular stress signals to control survival, differentiation, and organelle quality across diverse tissues. Its expression is regulated at multiple levels: translationally via eIF2α phosphorylation-dependent bypass of inhibitory uORFs in its 5′-UTR, with an additional nonsense-mediated mRNA decay layer targeting uORF2-containing transcripts [PMID:18195013, PMID:18055463, PMID:23876217]; and post-translationally via N-terminal ubiquitinylation by the E2 enzyme Cdc34, counteracted by HSP70-mediated stabilization and NLK/TAK1-dependent protection from proteasomal degradation [PMID:18458088, PMID:21521685, PMID:25512613]. As a transcription factor, ATF5 activates pro-survival targets including MCL1 and BCL-2 downstream of oncogenic (RAS/MAPK–CREB3L2, BCR-ABL/PI3K/AKT) and stress (mitochondrial UPR, ER stress) signaling pathways, while also functioning as a structural centrosomal protein that forms a 9-fold ring at the mother centriole to scaffold pericentriolar material assembly in a SUMOylation-regulated, cell-cycle-dependent manner [PMID:20495567, PMID:21212266, PMID:27426517, PMID:26213385, PMID:29326161]."},"prefetch_data":{"uniprot":{"accession":"Q9Y2D1","full_name":"Cyclic AMP-dependent transcription factor ATF-5","aliases":["Activating transcription factor 5","Transcription factor ATFx"],"length_aa":282,"mass_kda":30.7,"function":"Transcription factor that either stimulates or represses gene transcription through binding of different DNA regulatory elements such as cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), ATF5-specific response element (ARE) (consensus: 5'-C[CT]TCT[CT]CCTT[AT]-3') but also the amino acid response element (AARE), present in many viral and cellular promoters. Critically involved, often in a cell type-dependent manner, in cell survival, proliferation, and differentiation (PubMed:10373550, PubMed:15358120, PubMed:20654631, PubMed:21212266). Its transcriptional activity is enhanced by CCND3 and slightly inhibited by CDK4 (PubMed:15358120). Important regulator of the cerebral cortex formation, functions in cerebral cortical neuroprogenitor cells to maintain proliferation and to block differentiation into neurons. Must be down-regulated in order for such cells to exit the cycle and differentiate (By similarity). Participates in the pathways by which SHH promotes cerebellar granule neuron progenitor cells proliferation (By similarity). Critical for survival of mature olfactory sensory neurons (OSN), directs expression of OSN-specific genes (By similarity). May be involved in osteogenic differentiation (PubMed:22442021). Promotes cell proliferation and survival by inducing the expression of EGR1 sinergistically with ELK1. Once acetylated by EP300, binds to ARE sequences on target genes promoters, such as BCL2 and EGR1 (PubMed:21791614). Plays an anti-apoptotic role through the transcriptional regulation of BCL2, this function seems to be cell type-dependent (By similarity). Cooperates with NR1I3/CAR in the transcriptional activation of CYP2B6 in liver (PubMed:18332083). In hepatic cells, represses CRE-dependent transcription and inhibits proliferation by blocking at G2/M phase (PubMed:18701499, PubMed:22528486). May act as a negative regulator of IL1B transduction pathway in liver (PubMed:24379400). Upon IL1B stimulus, cooperates with NLK to activate the transactivation activity of C/EBP subfamily members (PubMed:25512613). Besides its function of transcription factor, acts as a cofactor of CEBPB to activate CEBPA and promote adipocyte differentiation (PubMed:24216764). Regulates centrosome dynamics in a cell-cycle- and centriole-age-dependent manner. Forms 9-foci symmetrical ring scaffold around the mother centriole to control centrosome function and the interaction between centrioles and pericentriolar material (PubMed:26213385)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9Y2D1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATF5","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATF5","total_profiled":1310},"omim":[{"mim_id":"615903","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 10; CHCHD10","url":"https://www.omim.org/entry/615903"},{"mim_id":"606398","title":"ACTIVATING TRANSCRIPTION FACTOR 5; ATF5","url":"https://www.omim.org/entry/606398"},{"mim_id":"605210","title":"DISC1 SCAFFOLD PROTEIN; DISC1","url":"https://www.omim.org/entry/605210"},{"mim_id":"137800","title":"GLIOMA SUSCEPTIBILITY 1; GLM1","url":"https://www.omim.org/entry/137800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":2375.4}],"url":"https://www.proteinatlas.org/search/ATF5"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2D1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2D1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2D1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2D1-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATF5","jax_strain_url":"https://www.jax.org/strain/search?query=ATF5"},"sequence":{"accession":"Q9Y2D1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2D1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2D1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2D1"}},"corpus_meta":[{"pmid":"27426517","id":"PMC_27426517","title":"The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.","date":"2016","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/27426517","citation_count":516,"is_preprint":false},{"pmid":"18195013","id":"PMC_18195013","title":"Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18195013","citation_count":243,"is_preprint":false},{"pmid":"23761072","id":"PMC_23761072","title":"CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23761072","citation_count":185,"is_preprint":false},{"pmid":"20495567","id":"PMC_20495567","title":"A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications.","date":"2010","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20495567","citation_count":148,"is_preprint":false},{"pmid":"18055463","id":"PMC_18055463","title":"Stress-induced translation of ATF5 mRNA is regulated by the 5'-untranslated region.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18055463","citation_count":119,"is_preprint":false},{"pmid":"21715304","id":"PMC_21715304","title":"BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21715304","citation_count":119,"is_preprint":false},{"pmid":"12805299","id":"PMC_12805299","title":"Regulated expression of ATF5 is required for the progression of neural progenitor cells to neurons.","date":"2003","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12805299","citation_count":116,"is_preprint":false},{"pmid":"31274354","id":"PMC_31274354","title":"Cardioprotection by the mitochondrial unfolded protein response requires ATF5.","date":"2019","source":"American journal of physiology. 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ATF5 expression rescues UPRmt signaling in atfs-1-deficient C. elegans via the same UPRmt promoter element, demonstrating functional conservation.\",\n      \"method\": \"Cell fractionation, C. elegans genetic rescue, mammalian cell knockdown with mitochondrial stress assays, transcriptional reporter assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, genetic rescue, knockdown + phenotypic readout) in a single high-impact study, replicated conceptually in multiple downstream studies\",\n      \"pmids\": [\"27426517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATF5 protein expression is translationally upregulated in response to diverse stresses (ER stress, arsenite, proteasome inhibition) via eIF2α phosphorylation. The ATF5 5'-UTRα contains two uORFs analogous to ATF4: uORF1 is positive-acting allowing reinitiation, while uORF2 is inhibitory under normal conditions; eIF2 phosphorylation during stress permits ribosomes to bypass uORF2 and translate the ATF5 coding region. ATF4 also contributes to basal ATF5 mRNA transcription.\",\n      \"method\": \"Polyribosome fractionation, luciferase reporter mutagenesis of 5'-UTR uORFs, ATF4 knockout MEF analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted translational mechanism with mutational analysis, replicated and consistent with parallel study (PMID:18055463)\",\n      \"pmids\": [\"18195013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ATF5 mRNA translation is regulated by alternative 5'-UTRs (5'-UTRα and 5'-UTRβ): 5'-UTRα represses translation under normal conditions, and this repression is relieved by amino acid limitation or arsenite via eIF2α phosphorylation. Mutation of uAUG2 in uORF2 abolishes stress-induced translational upregulation.\",\n      \"method\": \"Luciferase reporter assay with 5'-UTR mutants, eIF2α phosphorylation analysis, heme-regulated inhibitor kinase overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reporter system with mutagenesis, consistent with PMID:18195013\",\n      \"pmids\": [\"18055463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CHOP directly induces ATF5 transcription in response to proteasome inhibition; ATF5 in turn activates pro-apoptotic targets including NOXA, creating a feedforward loop. Both ATF4 and CHOP directly transcriptionally activate ATF5. ATF5 knockdown increases cell survival during proteasome inhibition, indicating a pro-apoptotic function.\",\n      \"method\": \"Promoter reporter assays, siRNA knockdown, transcriptome analysis, cell viability assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (transcriptomics, reporter assays, knockdown + survival readout) in single study\",\n      \"pmids\": [\"23761072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In malignant glioma, RAS-MAPK or PI3K signaling activates CREB3L2, which directly activates ATF5 transcription; ATF5 in turn promotes survival by stimulating transcription of MCL1, an anti-apoptotic BCL-2 family member.\",\n      \"method\": \"Genome-wide RNAi screen, chromatin immunoprecipitation, reporter assays, siRNA knockdown, mouse xenograft models\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide unbiased screen with ChIP and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"20495567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BCR-ABL suppresses autophagy through the PI3K/AKT/FOXO4 pathway, which transcriptionally upregulates ATF5; ATF5 then stimulates transcription of mTOR, a master negative regulator of autophagy. Imatinib-induced autophagy results from inhibition of this BCR-ABL/PI3K/AKT/FOXO4/ATF5/mTOR pathway.\",\n      \"method\": \"Reporter assays, ChIP, siRNA knockdown, pharmacological inhibition, BCR-ABL transformed cell lines\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including ChIP, reporter assays, and epistasis experiments\",\n      \"pmids\": [\"21715304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ATF5 promotes neuroprogenitor cell expansion and blocks differentiation into neurons; NGF downregulates ATF5 protein and transcripts, and exogenous ATF5 suppresses NGF-promoted neurite outgrowth requiring CRE site repression. Dominant-negative ATF5 or siRNA targeting ATF5 accelerates neurogenesis.\",\n      \"method\": \"PC12 cell overexpression/knockdown, dominant-negative ATF5, siRNA, clonal neurosphere cultures, NGF treatment\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple loss- and gain-of-function approaches with defined cellular phenotype\",\n      \"pmids\": [\"12805299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BCL-2 is a direct downstream transcriptional target of ATF5: ATF5 binds to an ATF5-specific regulatory element downstream of the BCL-2 P2 promoter to stimulate BCL-2 expression in C6 glioma and MCF-7 breast cancer cells but not in non-transformed cells, explaining cell-type-dependent survival function.\",\n      \"method\": \"Promoter reporter assays, electrophoretic mobility shift assay (EMSA), ChIP, siRNA knockdown, dominant-negative ATF5\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated by EMSA and ChIP, functional validation by knockdown and rescue\",\n      \"pmids\": [\"21212266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATF5 interacts with the transcriptional coactivator p300, which acetylates ATF5 at lysine-29; this acetylation enhances ATF5-p300 interaction and binding to the ATF5 response element (ARE) in the Egr-1 promoter. The ATF5/p300 complex then acetylates histone H3 at K14 at both ARE and SRE regions, facilitating ERK-phosphorylated Elk-1 binding and activating Egr-1 transcription.\",\n      \"method\": \"Co-IP, in vitro acetylation assays, ChIP, mutagenesis of acetylation sites, reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro acetylation assay, ChIP, mutagenesis, co-IP — multiple orthogonal methods\",\n      \"pmids\": [\"21791614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HSP70 interacts with the N-terminal activation domain of ATF5 (which is proline-rich) in an ATP-driven, ATPase-dependent manner. HSP70 binding stabilizes ATF5 protein against proteasome- and caspase-dependent degradation; HSP70 depletion accelerates ATF5 degradation and reduces downstream BCL-2 and Egr-1 expression.\",\n      \"method\": \"Co-IP, overexpression/knockdown, proteasome inhibitor experiments, ATPase mutant HSP70\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with mechanistic domain mapping, ATPase mutant validation, functional consequences\",\n      \"pmids\": [\"21521685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nucleophosmin (NPM1/B23) was identified by tandem affinity purification/mass spectrometry as an ATF5-interacting protein; NPM1 binds ATF5 via its C-terminal region (nucleolar localization domain) interacting with the ATF5 bZIP domain. NPM1 binding promotes ATF5 polyubiquitination and degradation via proteasome- and caspase-dependent pathways, displacing HSP70 from ATF5. NPM1-c mutant lacking nucleolar localization fails to degrade ATF5.\",\n      \"method\": \"Tandem affinity purification, mass spectrometry, co-IP, ubiquitination assays, NPM1-c mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — unbiased TAP-MS identification with mechanistic follow-up including mutant analysis and ubiquitination assays\",\n      \"pmids\": [\"22528486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATF5 forms a 9-fold symmetrical ring structure at the proximal end of the mother centriole in the inner layer of the pericentriolar material (PCM). ATF5 interacts with polyglutamylated tubulin on the mother centriole and with pericentrin (PCNT) in the PCM, controlling centriole-PCM interaction in a cell-cycle- and centriole-age-dependent manner. ATF5 depletion blocks PCM accumulation, causes centriole fragmentation, and leads to multipolar mitotic spindles and genomic instability.\",\n      \"method\": \"Super-resolution microscopy (structured illumination), co-IP, siRNA knockdown, cell cycle synchronization, immunofluorescence\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural characterization by super-resolution microscopy plus co-IP and loss-of-function with multiple phenotypic readouts\",\n      \"pmids\": [\"26213385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATF5 is SUMO2/3-modified at a conserved consensus site; SUMOylation is elevated in G1 phase and diminished in G2/M phase. SUMOylation disrupts ATF5 interaction with centrosomal proteins and dislodges ATF5 from the centrosome at end of M phase. Blocking ATF5 SUMOylation deregulates the centrosome cycle, prevents ATF5 translocation from the centrosome, and causes genomic instability and G2/M arrest.\",\n      \"method\": \"SUMO modification assay, co-IP, cell cycle synchronization, mutagenesis of SUMO consensus site, centrosome localization by immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical PTM identification with site mutagenesis and functional consequence on centrosome cycle\",\n      \"pmids\": [\"29326161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATF5 protein is degraded via the ubiquitin-proteasome pathway through N-terminal ubiquitinylation at the free amino group of the N-terminal methionine. Cisplatin stabilizes ATF5 by promoting nucleus-to-cytoplasm translocation of E2 ubiquitin-conjugating enzyme Cdc34, reducing the interaction between ATF5 and Cdc34.\",\n      \"method\": \"Ubiquitination assays, N-terminal tagging experiments, Cdc34 localization analysis, co-IP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic dissection of ubiquitination site with functional mutants and identification of E2 enzyme\",\n      \"pmids\": [\"18458088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In glioma, the endoplasmic reticulum stress transducer BBF2H7 directly activates ATF5 transcription; ATF5 in turn activates MCL1 transcription to suppress ER stress-induced apoptosis in chondrocytes. Loss of BBF2H7 leads to loss of ATF5 and MCL1, and increased apoptosis in proliferating chondrocytes.\",\n      \"method\": \"Bbf2h7 knockout mice, reporter assays, ChIP, immunostaining, TUNEL\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout mouse with mechanistic pathway dissection by ChIP and reporter assays\",\n      \"pmids\": [\"22936798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dominant-negative ATF5 (DN-ATF5) kills tumor cells by associating with and blocking the transcriptional activities of CEBPB and CEBPD (not exclusively ATF5 itself), as revealed by unbiased pull-down/mass spectrometry. CEBPB or CEBPD knockdown causes apoptosis of multiple cancer cell lines but not normal astrocytes. DN-ATF5 interferes with CEBPB/CEBPD homodimer and heterodimer formation.\",\n      \"method\": \"Pull-down with mass spectrometry, co-IP, siRNA knockdown, transcriptional reporter assays, cell viability\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — unbiased MS identification of interactors with functional validation by knockdown and reporter assays\",\n      \"pmids\": [\"31676720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATF5 5'-UTRα reduces ATF5 mRNA stability by making it a target of nonsense-mediated mRNA decay (NMD): uORF2 translation terminates 125 nt upstream of an exon junction, fulfilling NMD criteria. Knockdown of NMD factors Upf1/Upf2 stabilizes ATF5 mRNA in a uAUG2-dependent manner. Stress-induced eIF2α phosphorylation bypasses uORF2 and stabilizes ATF5 mRNA.\",\n      \"method\": \"Upf1/Upf2 siRNA knockdown, uAUG2 mutagenesis, mRNA stability assays, eIF2α phosphorylation analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mechanistic reconstitution with mutagenesis and NMD factor knockdown experiments\",\n      \"pmids\": [\"23876217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATF5 is required for terminal differentiation and survival of olfactory sensory neurons (OSNs): Atf5 knockout mice show massive reduction of mature OSNs due to a differentiation defect and induction of apoptosis. Atf5 is expressed in immature and all mature OSNs, and ectopic Atf5 expression in neural progenitor cells induces OSN-specific gene expression.\",\n      \"method\": \"Atf5 knockout mice, immunostaining with OSN markers, expression profiling, ectopic gene expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout mouse with defined cellular phenotype and marker analysis\",\n      \"pmids\": [\"23090999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PDX1 directly binds the Atf5 promoter (by ChIP-seq) and regulates ATF5 expression in β-cells. ATF5 is positioned downstream of and parallel to ATF4 in regulating 4EBP1, a mTOR pathway component that inhibits protein translation. ATF5 deficiency attenuates stress suppression of global translation, enhancing β-cell susceptibility to stress-induced apoptosis.\",\n      \"method\": \"ChIP-seq, siRNA knockdown, chromatin occupancy, loss-of-function in β-cell stress models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq for direct binding plus epistasis experiments and loss-of-function phenotype\",\n      \"pmids\": [\"28115692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pharmacological UPRmt induction is cardioprotective in an ATF5-dependent manner: in vivo UPRmt inducers protect against cardiac ischemia-reperfusion injury in wild-type but not global Atf5-/- mice. RNA-Seq revealed an ATF5-dependent gene set upregulated by UPRmt induction.\",\n      \"method\": \"Atf5 global knockout mice, ex vivo and in vivo ischemia-reperfusion injury model, RNA-Seq, qPCR/Western blot\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout mouse with in vivo functional phenotype and transcriptomics\",\n      \"pmids\": [\"31274354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NLK (Nemo-like kinase) interacts with ATF5 and inhibits its proteasome-dependent degradation in a kinase-independent manner. TAK1, acting upstream of NLK downstream of IL-1β, similarly stabilizes ATF5. NLK and ATF5 cooperate to activate C/EBP, and NLK cannot activate C/EBP upon ATF5 knockdown.\",\n      \"method\": \"Co-IP, NLK/ATF5 overexpression and knockdown, proteasome inhibition, luciferase reporter assay, NLK kinase-dead mutant\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with kinase-dead mutant, epistasis by knockdown, multiple readouts\",\n      \"pmids\": [\"25512613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATF5 protein is degraded via the ubiquitin-proteasome pathway; cadmium stabilizes ATF5 protein by interfering with a post-ubiquitination step of proteasomal degradation without reducing ubiquitination of ATF5. The N-terminal region contains a nuclear export signal but is not the ubiquitination site.\",\n      \"method\": \"Ubiquitination assays, proteasome inhibitor comparison, cadmium treatment, N-terminal deletion mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical dissection of degradation mechanism, single lab\",\n      \"pmids\": [\"19285020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATF5 overexpression in adult neurons reduces ER stress-induced apoptosis; ATF5 levels increase in hippocampal neurons upon ER stress (tunicamycin injection or kainate-induced status epilepticus). ATF5 induction occurs preferentially in neuronal fields resistant to apoptosis, suggesting a neuroprotective role.\",\n      \"method\": \"ATF5 overexpression/siRNA in primary neuronal cultures, in vivo status epilepticus model, in situ hybridization, immunohistochemistry\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function in neuronal cultures with apoptosis readout, supported by in vivo model\",\n      \"pmids\": [\"23518711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATF5 is a liver-enriched transcription factor that cooperates with constitutive androstane receptor (CAR) to transactivate CYP2B6; re-expression of ATF5 in HepG2 cells by adenoviral transduction markedly upregulates CYP2B6 mRNA. ATF5 and CYP2B6 are co-induced under ER stress conditions.\",\n      \"method\": \"Adenoviral transduction, qRT-PCR, cotransfection with CAR, ER stress induction\",\n      \"journal\": \"Drug metabolism and disposition: the biological fate of chemicals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, overexpression approach, moderate mechanistic follow-up\",\n      \"pmids\": [\"18332083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ATF5 activates asparagine synthetase (ASNS) promoter transcription via the nutrient-sensing response unit (NSRU) but not via CRE-containing elements. CHOP impairs ATF5-mediated or ATF4-mediated transcriptional activation of the ASNS promoter following amino acid deprivation.\",\n      \"method\": \"Promoter reporter assays (transient transfection), overexpression of ATF5 and CHOP\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay-based mechanism, single lab, no direct binding demonstrated\",\n      \"pmids\": [\"16164412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATF5 suppresses the transactivational activity of p53 and p63 as demonstrated by luciferase reporter assays; ATF5 gene transfer restores radioresistance in a radiosensitive clone that lost ATF5 expression.\",\n      \"method\": \"Luciferase reporter assay for p53/p21, ATF5 gene transfer, microarray, colony assay\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay with functional rescue, single lab, limited mechanistic detail on binding\",\n      \"pmids\": [\"19293535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human cytomegalovirus immediate-early protein IE86 physically interacts with and acetylates ATF5, promoting glioma cell survival. IE86 staining positively correlates with ATF5 staining in GBM samples.\",\n      \"method\": \"Co-IP, acetylation assay, overexpression, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with acetylation assay, single lab\",\n      \"pmids\": [\"28473657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATF5 is required for mitochondrial quality control in skeletal muscle: ATF5 KO mice show enlarged, less functional mitochondrial pools with enhanced biogenesis (increased PGC-1α), attenuated mitophagy, reduced antioxidant proteins, increased ROS emission, and blunted UPRmt gene expression response to acute exercise. Acute exercise enriches ATF5 in mitochondrial fractions rather than promoting nuclear translocation.\",\n      \"method\": \"ATF5 KO mice, subcellular fractionation, mitochondrial oxygen consumption/ROS assays, exercise protocol, Western blot, qPCR\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple organellar function readouts and fractionation experiments\",\n      \"pmids\": [\"36332794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATF5 promotes intestinal barrier function and a satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes leptin secretion. This mechanism protects against obesity-associated hyperglycemia that is detrimental to barrier function.\",\n      \"method\": \"ATF5 conditional and global knockout mice, enteric pathogen challenge, transcriptional analysis, hormone measurements\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout mouse with defined hormonal and metabolic pathway mechanism\",\n      \"pmids\": [\"36516750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMEM11 directly interacts with METTL1 and enhances m7G methylation of Atf5 mRNA, increasing ATF5 expression. ATF5 in turn promotes transcription of Inca1 (a CDK inhibitor), suppressing cardiomyocyte proliferation. TMEM11 deletion enhances cardiomyocyte proliferation and cardiac regeneration after injury.\",\n      \"method\": \"Co-IP, m7G MeRIP-seq, ATF5 overexpression, ChIP, siRNA knockdown, in vivo myocardial injury model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — epitranscriptomic mechanism identified by MeRIP-seq, co-IP, and in vivo genetic model\",\n      \"pmids\": [\"37286744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATF5 reciprocally interacts with Sonic hedgehog (Shh) signaling in cerebellar granule neuron progenitors (CGNPs): Shh promotes ATF5 expression via a post-transcriptional (protein stabilization) mechanism, and ATF5 in turn promotes Shh-stimulated CGNP proliferation and delays differentiation. Dominant-negative ATF5 diminishes Shh-stimulated CGNP proliferation.\",\n      \"method\": \"Dominant-negative ATF5, constitutive ATF5 expression in CGNPs, Shh treatment, BrdU proliferation assay, protein stability analysis\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"22095825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The ATF5 promoter was mapped to the region −105 to +3 relative to the transcription start site. EBF1 transcription factor binds to the ATF5 promoter and regulates ATF5 transcription in an EBF-binding-site-independent manner.\",\n      \"method\": \"Promoter deletion analysis, luciferase reporter assay, EBF1 binding analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay-based promoter mapping, single lab\",\n      \"pmids\": [\"20423929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATF5 protein is stabilized by IL-1β through its N-terminal hydrophobic amino acids, which serve as both a destabilization domain under steady-state conditions and an IL-1β response domain. IL-1β also increases ATF5 translational efficiency via 5'-UTRα and eIF2α phosphorylation. ATF5 negatively regulates IL-1β-induced SAA1 and SAA2 gene expression.\",\n      \"method\": \"N-terminal deletion/point mutants, protein stability assays, translational efficiency analysis, ATF5 siRNA knockdown, SAA1/SAA2 mRNA measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of stability domain with functional consequences, single lab\",\n      \"pmids\": [\"24379400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELF1 transcription factor binds to and activates the ATF5 gene promoter in glioma; ELF1 silencing inhibits glioma cell growth and migration via ATF5. Luciferase assay and ChIP confirm direct ELF1 binding to the ATF5 promoter.\",\n      \"method\": \"Luciferase reporter assay, ChIP, siRNA knockdown, bioinformatics\",\n      \"journal\": \"ACS chemical neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay with functional siRNA knockdown, single lab\",\n      \"pmids\": [\"33720698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT1 promotes neuroblastoma cell survival through ATF5: PRMT1 depletion decreases ATF5 expression and induces apoptosis, while ATF5 overexpression rescues apoptosis triggered by PRMT1 inhibition. ATF5 acts as a downstream effector of PRMT1-mediated survival signaling.\",\n      \"method\": \"siRNA/shRNA knockdown, PRMT1 inhibitor treatment, ATF5 overexpression rescue, in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis by rescue experiment, single lab with both in vitro and in vivo data\",\n      \"pmids\": [\"32415090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dominant-negative ATF5 rapidly depletes survivin (BIRC5) in tumor cells at both mRNA and protein levels. Survivin protein depletion is driven partly by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss precedes cell death but survivin overexpression does not rescue DN-ATF5-induced apoptosis, indicating multiple mechanisms.\",\n      \"method\": \"DN-ATF5 vector delivery, qRT-PCR, proteasome inhibitor rescue, USP9X analysis, overexpression rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple readouts for mechanism, single lab\",\n      \"pmids\": [\"31551409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 facilitates m6A modification of ATF5 mRNA, promoting its degradation. ATF5 overexpression reverses METTL14-mediated stemness inhibition in gastric cancer by increasing WDR74 transcription and enhancing β-catenin nuclear translocation. ATF5 directly binds and stimulates the WDR74 promoter as shown by ChIP and luciferase assays.\",\n      \"method\": \"MeRIP assay, luciferase reporter assay, ChIP, siRNA knockdown, Western blot\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP for epitranscriptomic mechanism, ChIP for direct ATF5 target binding, single lab\",\n      \"pmids\": [\"39497511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In obese female mice, suppressed AMPK activity increases the binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions, promoting replication of heteroplasmic mtDNA and impairing oocyte quality. AMPK activation blocks ATF5-POLG protein recruitment to mutated mtDNA.\",\n      \"method\": \"AMPK knockout mice, single-oocyte mtDNA sequencing, protein-DNA binding assays, AMPK activator treatment\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with direct protein-DNA binding measurements, single lab\",\n      \"pmids\": [\"38499990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Co-expression of C/EBPγ and ATF5 (but not either alone) increases Vmn2r66 (V2r) promoter reporter activity via the C/EBP:ATF response element (CARE) in Neuro2a cells, suggesting cooperative transcriptional activation in vomeronasal sensory neuron differentiation.\",\n      \"method\": \"Luciferase reporter assay with CARE site, co-transfection of C/EBPγ and ATF5\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single reporter assay approach, limited functional validation in vivo\",\n      \"pmids\": [\"31309319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATF5 is identified as a transcriptional regulator of Idh2 (isocitrate dehydrogenase-2) in skeletal muscle; AAV-mediated ATF5 overexpression reduced muscle fiber size and MyHC-IIB mRNA while increasing MyHC-IIA and Idh2 mRNA, suggesting fiber-type and metabolic gene regulation.\",\n      \"method\": \"AAV-mediated gene overexpression in mouse tibialis anterior, qRT-PCR, fiber type analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single overexpression approach without direct binding evidence, single lab\",\n      \"pmids\": [\"34611283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ASGR1 promotes monocyte-to-macrophage differentiation via upregulation of ATF5 through NF-κB/IKBa phosphorylation; ASGR1 directly interacts with ATF5 as shown by co-IP.\",\n      \"method\": \"Co-IP, siRNA knockdown/overexpression, Western blot, flow cytometry, in vivo LPS sepsis model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with in vivo genetic model, but mechanistic detail on ATF5 in this pathway is limited\",\n      \"pmids\": [\"36621538\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATF5 is a stress-responsive bZIP transcription factor whose activity is regulated at multiple levels: translationally via eIF2α phosphorylation-dependent bypass of inhibitory uORFs in its 5'-UTR, post-translationally via proteasomal degradation (involving N-terminal ubiquitinylation and the E2 enzyme Cdc34, counteracted by HSP70 stabilization and NLK/TAK1-mediated protection), acetylation by p300 (enhancing promoter binding), and SUMOylation (controlling centrosomal localization); it functions as a nuclear transcription factor activating survival genes (MCL1, BCL-2, Egr-1, mTOR, CYP2B6, cholecystokinin) downstream of stress pathways including the mitochondrial UPR, integrated stress response, and oncogenic signaling (RAS/MAPK-CREB3L2, BCR-ABL/PI3K/AKT/FOXO4), and also serves as a structural centrosomal protein forming a 9-fold ring at the mother centriole to scaffold pericentriolar material assembly via interactions with polyglutamylated tubulin and pericentrin.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATF5 is a stress-responsive bZIP transcription factor that integrates cellular stress signals to control survival, differentiation, and organelle quality across diverse tissues. Its expression is regulated at multiple levels: translationally via eIF2α phosphorylation-dependent bypass of inhibitory uORFs in its 5′-UTR, with an additional nonsense-mediated mRNA decay layer targeting uORF2-containing transcripts [PMID:18195013, PMID:18055463, PMID:23876217]; and post-translationally via N-terminal ubiquitinylation by the E2 enzyme Cdc34, counteracted by HSP70-mediated stabilization and NLK/TAK1-dependent protection from proteasomal degradation [PMID:18458088, PMID:21521685, PMID:25512613]. As a transcription factor, ATF5 activates pro-survival targets including MCL1 and BCL-2 downstream of oncogenic (RAS/MAPK–CREB3L2, BCR-ABL/PI3K/AKT) and stress (mitochondrial UPR, ER stress) signaling pathways, while also functioning as a structural centrosomal protein that forms a 9-fold ring at the mother centriole to scaffold pericentriolar material assembly in a SUMOylation-regulated, cell-cycle-dependent manner [PMID:20495567, PMID:21212266, PMID:27426517, PMID:26213385, PMID:29326161].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing ATF5 as a neural progenitor maintenance factor resolved how bZIP transcription factors control the proliferation-to-differentiation switch in neurogenesis.\",\n      \"evidence\": \"Overexpression, dominant-negative, and siRNA approaches in PC12 cells and neurosphere cultures with NGF treatment\",\n      \"pmids\": [\"12805299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct transcriptional targets mediating the anti-differentiation effect were not identified\",\n        \"No in vivo loss-of-function model at that time\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that ATF5 translation is controlled by eIF2α phosphorylation-dependent bypass of inhibitory uORFs in its 5′-UTR established ATF5 as a member of the ISR-regulated translational program alongside ATF4.\",\n      \"evidence\": \"Luciferase reporters with uORF mutagenesis, eIF2α kinase overexpression, polyribosome fractionation in mammalian cells\",\n      \"pmids\": [\"18055463\", \"18195013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contributions of 5′-UTRα versus 5′-UTRβ in different tissues not resolved\",\n        \"Whether additional kinases beyond HRI regulate this switch in vivo\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying N-terminal ubiquitinylation via the E2 enzyme Cdc34 as the primary ATF5 degradation mechanism explained how ATF5 protein is kept at low steady-state levels and how genotoxic stress (cisplatin) stabilizes ATF5.\",\n      \"evidence\": \"Ubiquitination assays, N-terminal tagging, Cdc34 localization analysis, co-IP in mammalian cells\",\n      \"pmids\": [\"18458088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The E3 ubiquitin ligase responsible was not identified\",\n        \"Whether N-terminal ubiquitinylation applies in all cell types\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A genome-wide RNAi screen placing ATF5 downstream of RAS-MAPK/CREB3L2 and upstream of MCL1 in glioma established the first oncogenic transcriptional cascade through which ATF5 promotes tumor survival.\",\n      \"evidence\": \"Genome-wide RNAi screen, ChIP, reporter assays, mouse xenograft models in malignant glioma\",\n      \"pmids\": [\"20495567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CREB3L2–ATF5–MCL1 axis operates in non-glioma cancers\",\n        \"Structural basis of ATF5 binding to the MCL1 promoter\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Multiple studies in 2011 defined a layered post-translational regulatory network: HSP70 stabilizes ATF5 against proteasomal/caspase degradation, p300 acetylates ATF5 at K29 to enhance promoter binding, and ATF5 directly transactivates BCL-2 and Egr-1, clarifying how ATF5 protein activity is fine-tuned and which survival genes it controls.\",\n      \"evidence\": \"Reciprocal co-IP with domain mapping and ATPase mutants (HSP70); in vitro acetylation, ChIP, and mutagenesis (p300/Egr-1); EMSA and ChIP for BCL-2 promoter binding\",\n      \"pmids\": [\"21521685\", \"21791614\", \"21212266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether acetylation and HSP70 binding are coordinated or competitive\",\n        \"Identity of deacetylase(s) reversing K29 acetylation\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking BCR-ABL to ATF5-mediated mTOR transcription and autophagy suppression revealed an oncogene–ATF5–mTOR axis controlling autophagy in CML.\",\n      \"evidence\": \"ChIP, reporter assays, siRNA epistasis, pharmacological inhibition in BCR-ABL-transformed cells\",\n      \"pmids\": [\"21715304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ATF5 activates mTOR transcription in non-leukemic contexts\",\n        \"Direct ATF5 binding site on the mTOR promoter not mapped at nucleotide resolution\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"NPM1 was identified as an ATF5 interactor that displaces HSP70 and promotes ATF5 polyubiquitination and degradation, with NPM1-c AML mutant failing to do so—connecting ATF5 stability to nucleolar integrity and AML pathogenesis.\",\n      \"evidence\": \"TAP-MS, co-IP, ubiquitination assays, NPM1-c mutant analysis\",\n      \"pmids\": [\"22528486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NPM1-c-mediated ATF5 stabilization contributes to leukemogenesis in vivo\",\n        \"Stoichiometry of the HSP70–ATF5–NPM1 competition\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Atf5 knockout mice revealed that ATF5 is essential for terminal differentiation and survival of olfactory sensory neurons, establishing a non-cancer developmental role.\",\n      \"evidence\": \"Atf5 knockout mice with OSN marker immunostaining and ectopic expression in neural progenitors\",\n      \"pmids\": [\"23090999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct transcriptional targets of ATF5 driving OSN fate commitment not comprehensively identified\",\n        \"Whether ATF5 cooperates with other bZIP factors in OSN specification\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two discoveries added regulatory depth: CHOP directly activates ATF5 transcription creating a feedforward pro-apoptotic loop during proteasome inhibition, and ATF5 mRNA is subject to NMD via uORF2, adding an mRNA stability layer to stress-responsive ATF5 induction.\",\n      \"evidence\": \"Promoter reporters and siRNA with cell viability readouts (CHOP); Upf1/Upf2 knockdown with uAUG2 mutagenesis and mRNA stability assays (NMD)\",\n      \"pmids\": [\"23761072\", \"23876217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NMD regulation of ATF5 contributes to tissue-specific expression patterns\",\n        \"Relative contribution of translational versus NMD regulation under different stresses\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Super-resolution imaging revealed an entirely unexpected structural role: ATF5 forms a 9-fold symmetrical ring at the proximal end of the mother centriole, scaffolding PCM assembly through interactions with polyglutamylated tubulin and pericentrin, and its loss causes centriole fragmentation and genomic instability.\",\n      \"evidence\": \"Structured illumination microscopy, co-IP, siRNA knockdown, cell cycle synchronization\",\n      \"pmids\": [\"26213385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How a bZIP transcription factor structurally integrates into the centriole wall\",\n        \"Whether centrosomal and nuclear/transcriptional functions are coordinated or independent\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"ATF5 was established as the mammalian mediator of the mitochondrial UPR: normally sequestered in mitochondria, it accumulates in the cytosol and nucleus during mitochondrial stress, functionally rescuing C. elegans atfs-1 loss.\",\n      \"evidence\": \"Cell fractionation, C. elegans genetic rescue, knockdown with mitochondrial stress assays\",\n      \"pmids\": [\"27426517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Import/export mechanism controlling ATF5 mitochondrial sequestration\",\n        \"Whether ATF5 directly senses mitochondrial protein misfolding or responds to secondary signals\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that SUMO2/3 modification of ATF5 dislodges it from the centrosome at the end of M phase resolved how the centrosomal and nuclear pools of ATF5 are cell-cycle-regulated.\",\n      \"evidence\": \"SUMO modification assay, SUMO-site mutagenesis, cell cycle synchronization, centrosome immunofluorescence\",\n      \"pmids\": [\"29326161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the SUMO E3 ligase and SENP deconjugase controlling ATF5 SUMOylation\",\n        \"Whether deSUMOylated ATF5 released from centrosomes enters the nucleus to function as a transcription factor\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Unbiased pull-down/MS revealed that dominant-negative ATF5 kills tumor cells primarily by blocking CEBPB and CEBPD transcriptional activity rather than ATF5 alone, reinterpreting the mechanism of the anti-cancer DN-ATF5 tool.\",\n      \"evidence\": \"Pull-down with mass spectrometry, co-IP, siRNA knockdown, cell viability assays\",\n      \"pmids\": [\"31676720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether endogenous ATF5 normally heterodimerizes with CEBPB/CEBPD to regulate shared targets\",\n        \"Therapeutic implications require validation in patient-derived models\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In vivo ischemia-reperfusion studies in Atf5−/− mice demonstrated that pharmacological UPRmt induction is cardioprotective in an ATF5-dependent manner, extending ATF5's UPRmt role to cardiac protection.\",\n      \"evidence\": \"Atf5 global knockout mice, ex vivo and in vivo cardiac ischemia-reperfusion models, RNA-Seq\",\n      \"pmids\": [\"31274354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"ATF5-dependent cardioprotective gene targets not fully characterized\",\n        \"Whether ATF5 operates through the same mitochondria-to-nucleus translocation in cardiomyocytes\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Atf5 KO mice revealed that ATF5 is required for mitochondrial quality control in skeletal muscle—governing mitophagy, antioxidant defense, and UPRmt gene induction during exercise—extending its organelle maintenance role beyond the heart.\",\n      \"evidence\": \"ATF5 KO mice, subcellular fractionation, mitochondrial respiration and ROS assays, exercise protocol\",\n      \"pmids\": [\"36332794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether exercise enrichment of ATF5 in mitochondrial fractions reflects import or membrane association\",\n        \"Tissue-specific versus systemic consequences of ATF5 loss on exercise adaptation\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Conditional knockout studies showed ATF5 transcriptionally activates cholecystokinin to promote intestinal barrier function and satiety, revealing a gut endocrine role distinct from its stress-response functions.\",\n      \"evidence\": \"ATF5 conditional and global KO mice, enteric pathogen challenge, hormone measurements\",\n      \"pmids\": [\"36516750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ATF5 directly binds the cholecystokinin promoter\",\n        \"How intestinal ATF5 expression is regulated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of METTL1-mediated m7G methylation of Atf5 mRNA as a mechanism enhancing ATF5 expression, with ATF5 then activating the CDK inhibitor Inca1 to suppress cardiomyocyte proliferation, connected epitranscriptomics to ATF5-dependent cell cycle control in the heart.\",\n      \"evidence\": \"m7G MeRIP-seq, co-IP, ChIP, siRNA, in vivo myocardial injury model\",\n      \"pmids\": [\"37286744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether m7G modification of ATF5 mRNA occurs in non-cardiac contexts\",\n        \"Whether Inca1 is a direct or indirect ATF5 target in other proliferative tissues\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATF5's dual roles as a nuclear transcription factor and a structural centrosomal protein are coordinated—including the signals partitioning ATF5 among mitochondria, centrosome, and nucleus, and the E3 ligase(s) controlling its N-terminal ubiquitinylation—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"E3 ubiquitin ligase for ATF5 not identified\",\n        \"Mechanism of ATF5 import into mitochondria and its release during stress unclear\",\n        \"Whether centrosomal ATF5 pool and transcription factor pool derive from distinct translation or post-translational sorting events\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 5, 7, 8, 17, 28, 29, 36]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 8, 29, 36]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 8, 17]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 27]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 5, 7, 8, 17, 28, 29]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 2, 3, 19, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 4, 7, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 17, 30]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 12, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 30]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [11, 12, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 10, 13, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HSPA1A\",\n      \"NPM1\",\n      \"EP300\",\n      \"PCNT\",\n      \"NLK\",\n      \"CEBPB\",\n      \"CEBPD\",\n      \"CDC34\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}