{"gene":"MAP1LC3B","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2003,"finding":"MAP1LC3B undergoes a distinct post-translational modification compared to MAP1LC3A and MAP1LC3C: it does not undergo C-terminal cleavage after the conserved Gly-120 residue, and instead is modified at Lys-122. All three isoforms associate with autophagosomal membranes as shown by subcellular fractionation and immunofluorescence.","method":"Cell fractionation, immunofluorescence, biochemical characterization of post-translational modifications","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, immunofluorescence, biochemical modification mapping) in a single study; later contradicted/refined by PMID:15355958","pmids":["12740394"],"is_preprint":false},{"year":2004,"finding":"The C-terminal Met-121 of MAP1LC3B is cleaved by human Atg4B to expose Gly-120, which is essential for subsequent ubiquitylation-like reactions: formation of Atg7-MAP1LC3B (E1-like) and Atg3-MAP1LC3B (E2-like) intermediates, and conjugation to phospholipid (PE). Gly-120 is required for both C-terminal cleavage and lipidation. RNA interference of MAP1LC3B mRNA decreased both endogenous MAP1LC3B-PL and total MAP1LC3B protein.","method":"In vitro cleavage assay with recombinant Atg4B, site-directed mutagenesis (G120A mutant), RNAi knockdown, cell fractionation, immunoprecipitation of enzyme-substrate intermediates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis, multiple orthogonal methods (in vitro assay, mutagenesis, RNAi, fractionation) in a single rigorous study","pmids":["15355958"],"is_preprint":false},{"year":2009,"finding":"Hypoxia increases transcription of MAP1LC3B through the transcription factor ATF4, which is regulated by the PERK arm of the UPR. This transcriptional induction replenishes MAP1LC3B protein consumed during extensive autophagy. Cells deficient in PERK signaling fail to induce MAP1LC3B transcription and become depleted of MAP1LC3B protein during hypoxia.","method":"Transcriptional reporter assays, western blotting, PERK-deficient cell lines, human tumor xenografts with immunostaining","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines and in vivo xenograft model, but mechanism inferred from loss-of-function (PERK KO) and expression measurements without direct promoter binding demonstrated for MAP1LC3B","pmids":["20038797"],"is_preprint":false},{"year":2014,"finding":"HCV core protein activates autophagy through UPR pathways: DDIT3/CHOP directly binds to the -253 to -99 base region of the MAP1LC3B promoter to upregulate its transcription. The EIF2AK3/ATF4 pathway upregulates ATG12 but not MAP1LC3B.","method":"Luciferase reporter assay, chromatin immunoprecipitation/promoter binding assay, western blotting, qPCR in Huh7 cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated and reporter assay performed, single lab","pmids":["24589849"],"is_preprint":false},{"year":2013,"finding":"PGRMC1/S2R (progesterone receptor membrane component 1) physically associates with MAP1LC3 and UVRAG. PGRMC1 is required for autophagy-dependent degradation of ubiquitinated proteins and damaged organelles; its inhibition by RNAi or small molecules causes accumulation of autophagy substrates and aberrant mitochondria.","method":"Co-immunoprecipitation, RNAi knockdown, small-molecule inhibition, western blotting for autophagy substrates","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional RNAi with substrate accumulation readout, single lab, two orthogonal approaches","pmids":["24113030"],"is_preprint":false},{"year":2016,"finding":"The cochaperone BAG3 controls the basal amount of MAP1LC3B protein by regulating translation of its mRNA, not its transcription. BAG3 knockdown reduced total LC3B protein without affecting LC3B mRNA levels or LC3B lipidation induced by starvation or proteasome inhibition. This effect appeared specific to LC3B among ATG proteins tested.","method":"RNAi knockdown, western blotting, RT-qPCR, polysome profiling/translational analysis in HeLa and HEK293 cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (transcriptional vs. translational assays, knockdown), single lab","pmids":["26654586"],"is_preprint":false},{"year":2019,"finding":"pVHL (Von Hippel-Lindau protein) interacts with MAP1LC3B via an LIR motif in its beta domain and ubiquitinates MAP1LC3B, thereby inhibiting LC3B-mediated autophagy. The L101A VHL mutant fails to interact with MAP1LC3B and fails to induce its ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (L101A), western blotting in VHL-deficient and VHL-expressing RCC cell lines","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis validation and functional ubiquitination assay, single lab","pmids":["30902965"],"is_preprint":false},{"year":2015,"finding":"MAP1LC3B deficiency in mice leads to failure to upregulate autophagosome formation in dendritic cells upon RSV infection, resulting in IL-1β and IL-6 secretion and enhanced IL-17a-dependent lung pathology. Both hematopoietic and structural cell LC3B deficiency contribute to this phenotype, as shown by bone marrow chimeras.","method":"LC3b knockout mice, bone marrow chimeras, RSV infection model, cytokine measurements, in vitro DC assays","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with bone marrow chimera epistasis and defined cytokine phenotype, single lab","pmids":["25669150"],"is_preprint":false},{"year":2019,"finding":"LC3B knockout mice show susceptibility to bleomycin-induced lung injury and fibrosis. LC3B knockdown sensitizes lung epithelial cells to bleomycin-induced apoptosis while its overexpression is protective. Cathepsin A was identified as a novel LC3B-binding partner; its overexpression drives lung epithelial cell apoptosis and it accumulates in aged LC3B-/- mice and IPF patient lungs.","method":"LC3B knockout mice, bleomycin lung fibrosis model, RNAi knockdown and overexpression in MLE12 cells, co-immunoprecipitation (cathepsin A binding), electron microscopy, proteasomal activity assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo phenotype, Co-IP for novel binding partner, in vitro functional overexpression/knockdown, single lab","pmids":["31431059"],"is_preprint":false},{"year":2020,"finding":"MAP1LC3B has a non-autophagic function upstream of procaspase-8 cleavage that contributes to ER stress-induced apoptosis triggered by thapsigargin. ATF4 and CHOP independently regulate MAP1LC3B protein upregulation in this context, and this function is required for optimal cytotoxicity in prostate and colon cancer cells.","method":"RNAi knockdown, western blotting, caspase activity assays, propidium iodide staining for cell death, real-time RT-PCR in LNCaP and HCT116 cells","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with defined apoptotic phenotype in two cell lines, multiple orthogonal methods, single lab","pmids":["31987044"],"is_preprint":false},{"year":2025,"finding":"HDAC6 physically interacts with MAP1LC3B and mediates its monoubiquitination, reducing MAP1LC3B protein levels and impairing autophagy. This promotes pathological cardiac hypertrophy. HDAC6 inhibition restores MAP1LC3B expression and autophagy, attenuating ISO-induced cardiac hypertrophy in mice.","method":"Co-immunoprecipitation, ubiquitination assay, HDAC6 overexpression and inhibition, ISO-induced cardiac hypertrophy mouse model, western blotting","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination assay and in vivo rescue experiment, single lab","pmids":["40212005"],"is_preprint":false},{"year":2022,"finding":"Ectopic expression of SQSTM1 and its MAP1LC3B-binding domain (LIR domain) targeted to the mitochondrial outer membrane directly induces mitophagy (forced mitophagy), capable of degrading approximately half of mitochondria and their DNA in HeLa cells and mouse embryos without apparent effects on mitochondrial membrane potential, ROS, mitosis, or embryo development.","method":"Ectopic expression of mitochondria-targeted SQSTM1 LIR domain, flow cytometry, fluorescence microscopy, mitochondrial DNA quantification in HeLa cells and mouse embryos","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in cells and embryos with domain-level resolution, single lab","pmids":["35574946"],"is_preprint":false},{"year":2024,"finding":"m6A RNA methylation of Map1lc3b mRNA, mediated by METTL3 (writer) and ALKBH5 (eraser), suppresses autophagic processes in Leydig cells exposed to BPA. Integrated transcriptomic and MeRIP-seq analysis identified Map1lc3b mRNA as a specific target of upregulated m6A modification induced by BPA.","method":"MeRIP-seq, RNA-seq integration, METTL3/ALKBH5 manipulation, in vivo and in vitro BPA exposure models, western blotting","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq with writer/eraser genetic manipulation and functional readout, single lab","pmids":["39662354"],"is_preprint":false},{"year":2025,"finding":"MAP1LC3B functions as an RNA-binding protein in early embryos and mediates maternal mRNA decay during the maternal-to-zygotic transition (MZT). LC3B-mediated mRNA decay operates with faster kinetics than the classical BTG4-CCR4-NOT pathway. Knockdown of LC3B or autophagy inhibition delays maternal mRNA clearance, impairs zygotic genome activation, and causes developmental arrest. Maternal Suv39h2 mRNA was identified as a key LC3B target.","method":"RIP-seq, RNA-seq, CUT&Tag in early embryos, LC3B knockdown, autophagy inhibition, developmental assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genomic and functional methods (RIP-seq, RNA-seq, CUT&Tag, knockdown with developmental phenotype), single lab","pmids":["41231099"],"is_preprint":false},{"year":2023,"finding":"IMP1 (IGF2BP1) colocalization with MAP1LC3B transcripts at homeostasis is reduced under stress. IMP1 deletion or mutation of IMP1 phosphorylation sites enhances MAP1LC3B expression at the protein level, promoting autophagy and intestinal stem cell regeneration.","method":"Single-molecule FISH, immunofluorescence, IMP1 knockout and phosphorylation-site mutant studies, organoid formation assay, in vivo irradiation regeneration model","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-molecule FISH colocalization with genetic and functional validation, single lab","pmids":["38081361"],"is_preprint":false},{"year":2024,"finding":"Protein ATG8ylation of MAP1LC3B (covalent conjugation to cellular proteins rather than lipids) requires E1-like ATG7 and E2-like ATG3, in common with lipid ATG8ylation, but is independent of the E3-like ATG12-ATG5-ATG16L1 complex (ATG5 knockout cells can still form ATG8ylated protein conjugates). ATG7 itself is identified as a target of MAP1LC3B ATG8ylation.","method":"CRISPR/Cas9 knockout cell lines (ATG5, ATG7, ATG3), deconjugation-resistant MAP1LC3B mutant (Q116P G120), western blotting, immunoprecipitation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with reconstitution-level mechanistic dissection, preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.07.03.601942"],"is_preprint":true},{"year":2025,"finding":"MAP1LC3B undergoes CASM (conjugation of ATG8 to single membranes) at the Golgi apparatus in TRIM46-deficient cells. This non-degradative Golgi Atg8ylation mechanistically resembles CASM. Genetic inhibition of CASM in TRIM46-deficient cells exacerbates Golgi morphology defects, and knockdown of CASM genes impairs Golgi reformation after drug-induced fragmentation, demonstrating that CASM contributes to Golgi repair.","method":"TRIM46 knockout cells, CASM gene knockdown, immunofluorescence colocalization (LC3B/GABARAP with TGOLN2), drug-induced Golgi fragmentation assay, TFEB activation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, preprint, colocalization and knockdown with morphological readout, no biochemical reconstitution","pmids":["bio_10.1101_2025.09.04.674289"],"is_preprint":true}],"current_model":"MAP1LC3B is a ubiquitin-like autophagy protein that is processed by Atg4B-mediated cleavage of its C-terminal Met-121 to expose Gly-120, which is then conjugated to phosphatidylethanolamine via Atg7 (E1) and Atg3 (E2) to form the lipidated LC3B-II form that associates with autophagosomal membranes; its transcription is induced by ATF4/CHOP downstream of the PERK-UPR arm, its translation is regulated by BAG3, and its protein stability is modulated by ubiquitination via HDAC6 and pVHL; beyond canonical autophagy, MAP1LC3B functions as an RNA-binding protein mediating maternal mRNA decay, participates in non-degradative CASM at endomembranes, and has non-autophagic roles in ER stress-induced apoptosis upstream of caspase-8."},"narrative":{"mechanistic_narrative":"MAP1LC3B is a ubiquitin-like protein central to autophagosome biogenesis that is matured through a conjugation cascade: human Atg4B cleaves its C-terminal Met-121 to expose Gly-120, which is then activated by the E1-like Atg7 and transferred via the E2-like Atg3 for conjugation to phospholipid (PE), generating the membrane-associated lipidated form essential for autophagy [PMID:15355958]. Gly-120 is strictly required for both cleavage and lipidation [PMID:15355958], and the protein associates with autophagosomal membranes [PMID:12740394]. Its abundance is controlled at multiple levels: ATF4 (downstream of the PERK arm of the UPR) drives transcription that replenishes MAP1LC3B consumed during hypoxic autophagy [PMID:20038797], CHOP/DDIT3 directly binds the MAP1LC3B promoter to upregulate transcription [PMID:24589849], the cochaperone BAG3 selectively controls its translation [PMID:26654586], and protein stability is restrained by LIR-dependent ubiquitination via pVHL [PMID:30902965] and monoubiquitination via HDAC6, which impairs autophagy and promotes cardiac hypertrophy [PMID:40212005]. The protein engages substrate-recruiting partners through LIR motifs, including SQSTM1, whose mitochondria-targeted LIR domain is sufficient to force mitophagy [PMID:35574946], and PGRMC1, required for autophagic clearance of ubiquitinated proteins and damaged organelles [PMID:24113030]. Beyond canonical degradative autophagy, MAP1LC3B acts upstream of procaspase-8 cleavage in ER stress-induced apoptosis [PMID:31987044], functions as an RNA-binding protein mediating rapid maternal mRNA decay during the maternal-to-zygotic transition [PMID:41231099], and can be covalently conjugated to proteins (ATG8ylation) via Atg7/Atg3 independently of the ATG12-ATG5-ATG16L1 complex [PMID:bio_10.1101_2024.07.03.601942]. Genetic loss in mice causes defects in dendritic-cell autophagy with exaggerated IL-17a-dependent lung pathology during RSV infection [PMID:25669150] and sensitizes lung epithelium to bleomycin-induced fibrosis [PMID:31431059].","teleology":[{"year":2003,"claim":"Established that MAP1LC3B is post-translationally modified and membrane-associated, distinguishing it biochemically from its paralogs and placing it on autophagosomal membranes.","evidence":"Cell fractionation, immunofluorescence, and biochemical modification mapping of three LC3 isoforms","pmids":["12740394"],"confidence":"Medium","gaps":["Initial claim of Lys-122 modification without C-terminal cleavage was refined by later reconstitution work","Enzymes mediating the modification not identified"]},{"year":2004,"claim":"Defined the core conjugation mechanism: Atg4B cleavage at Gly-120 licenses Atg7/Atg3-dependent lipidation to PE, answering how LC3B becomes membrane-competent.","evidence":"In vitro cleavage with recombinant Atg4B, G120A mutagenesis, RNAi, fractionation, and enzyme-substrate intermediate IP","pmids":["15355958"],"confidence":"High","gaps":["Does not address upstream membrane-targeting specificity","Regulation of the cascade in vivo not resolved"]},{"year":2009,"claim":"Showed that LC3B protein pools are transcriptionally replenished via PERK/ATF4 signaling during hypoxic autophagy, linking the UPR to autophagy capacity.","evidence":"Reporter assays, western blotting, PERK-deficient cells, and tumor xenografts","pmids":["20038797"],"confidence":"Medium","gaps":["Direct ATF4 binding to the MAP1LC3B promoter not demonstrated","Relative contribution of transcription vs. conjugation to autophagy output unquantified"]},{"year":2014,"claim":"Identified CHOP/DDIT3 as a direct transcriptional activator binding the MAP1LC3B promoter, distinguishing it from the ATF4 arm which acts on ATG12.","evidence":"Luciferase reporter, ChIP/promoter binding, qPCR, and western blotting in HCV-infected Huh7 cells","pmids":["24589849"],"confidence":"Medium","gaps":["Cooperativity between CHOP and ATF4 inputs not dissected","Context-dependence beyond HCV infection unknown"]},{"year":2016,"claim":"Revealed a translational control layer in which BAG3 selectively sets basal LC3B protein levels without affecting transcription or lipidation.","evidence":"RNAi, RT-qPCR, western blotting, and polysome profiling in HeLa and HEK293 cells","pmids":["26654586"],"confidence":"Medium","gaps":["Molecular mechanism by which BAG3 engages LC3B mRNA not defined","Specificity for LC3B among ATG mRNAs not fully mapped"]},{"year":2013,"claim":"Connected LC3B to substrate clearance through PGRMC1, which physically associates with it and is required for autophagic degradation of ubiquitinated proteins and damaged organelles.","evidence":"Co-IP, RNAi, small-molecule inhibition, and autophagy substrate readouts","pmids":["24113030"],"confidence":"Medium","gaps":["Direct vs. indirect nature of the LC3-PGRMC1 association unresolved","No reciprocal validation or structural basis"]},{"year":2019,"claim":"Established LIR-dependent ubiquitination of LC3B by pVHL as a negative regulator of LC3B-mediated autophagy.","evidence":"Co-IP, ubiquitination assay, and L101A mutagenesis in RCC cell lines","pmids":["30902965"],"confidence":"Medium","gaps":["Ubiquitin chain topology and fate of ubiquitinated LC3B unspecified","In vivo relevance not tested"]},{"year":2025,"claim":"Identified HDAC6-mediated monoubiquitination as a second ubiquitin-dependent route lowering LC3B levels, with pathological cardiac hypertrophy as the in vivo consequence.","evidence":"Co-IP, ubiquitination assay, HDAC6 overexpression/inhibition, and ISO-induced cardiac hypertrophy mouse model","pmids":["40212005"],"confidence":"Medium","gaps":["Whether HDAC6 acts as the ligase or a scaffold not clarified","Relationship to pVHL-mediated ubiquitination not addressed"]},{"year":2015,"claim":"Demonstrated in vivo that LC3B is required for dendritic-cell autophagy that restrains IL-17a-dependent lung immunopathology during RSV infection.","evidence":"LC3b knockout mice, bone marrow chimeras, RSV infection, and cytokine measurements","pmids":["25669150"],"confidence":"Medium","gaps":["Which autophagy substrates suppress inflammation unidentified","Mechanism linking LC3B loss to cytokine output undefined"]},{"year":2019,"claim":"Showed LC3B is protective against bleomycin lung injury and identified cathepsin A as a binding partner whose accumulation drives epithelial apoptosis.","evidence":"LC3B knockout mice, bleomycin model, knockdown/overexpression in MLE12 cells, Co-IP, and EM","pmids":["31431059"],"confidence":"Medium","gaps":["Whether cathepsin A is an autophagic degradation substrate of LC3B not established","Direct vs. indirect binding not resolved"]},{"year":2020,"claim":"Defined a non-autophagic role for LC3B acting upstream of procaspase-8 cleavage in ER stress-induced apoptosis, regulated by ATF4 and CHOP.","evidence":"RNAi, caspase activity assays, PI staining, and RT-PCR in LNCaP and HCT116 cells","pmids":["31987044"],"confidence":"Medium","gaps":["Molecular link between LC3B and procaspase-8 activation not mapped","Whether lipidation is required for this function unknown"]},{"year":2022,"claim":"Demonstrated that the LC3B-binding LIR domain of SQSTM1, when targeted to mitochondria, is sufficient to force mitophagy, establishing LIR-LC3B engagement as a deployable cargo-targeting module.","evidence":"Mitochondria-targeted SQSTM1 LIR expression, flow cytometry, microscopy, and mtDNA quantification in HeLa cells and mouse embryos","pmids":["35574946"],"confidence":"Medium","gaps":["Requirement for endogenous receptor selectivity bypassed by forced system","Generalizability to other organelles not tested"]},{"year":2024,"claim":"Showed that m6A methylation of Map1lc3b mRNA by METTL3/ALKBH5 suppresses autophagy, adding an epitranscriptomic regulatory layer.","evidence":"MeRIP-seq, RNA-seq integration, writer/eraser manipulation, and BPA exposure models","pmids":["39662354"],"confidence":"Medium","gaps":["Which reader proteins act on methylated Map1lc3b mRNA unidentified","Effect on translation vs. stability not separated"]},{"year":2024,"claim":"Established protein ATG8ylation of LC3B as a conjugation activity requiring Atg7/Atg3 but independent of the ATG12-ATG5-ATG16L1 complex, with ATG7 itself as a conjugation target.","evidence":"CRISPR ATG5/ATG7/ATG3 knockouts, deconjugation-resistant mutant, western blotting, and IP (preprint)","pmids":["bio_10.1101_2024.07.03.601942"],"confidence":"Medium","gaps":["Functional consequence of protein ATG8ylation not defined","Peer review pending; broader substrate range unknown"]},{"year":2025,"claim":"Identified LC3B as an RNA-binding protein driving rapid maternal mRNA decay during the maternal-to-zygotic transition, a function distinct from membrane autophagy.","evidence":"RIP-seq, RNA-seq, CUT&Tag, LC3B knockdown, and developmental assays in early embryos","pmids":["41231099"],"confidence":"Medium","gaps":["Structural basis of LC3B RNA binding undefined","Whether decay requires lipidation or the conjugation machinery unknown"]},{"year":2025,"claim":"Proposed that LC3B undergoes CASM at the Golgi to support Golgi repair in TRIM46-deficient cells, extending non-degradative ATG8ylation to organelle maintenance.","evidence":"TRIM46 knockout cells, CASM gene knockdown, colocalization, and Golgi fragmentation assays (preprint)","pmids":["bio_10.1101_2025.09.04.674289"],"confidence":"Low","gaps":["No biochemical reconstitution; colocalization-based","Single lab, preprint not peer-reviewed","Direct role of LC3B vs. GABARAP at the Golgi not separated"]},{"year":null,"claim":"How LC3B's diverse non-canonical activities (RNA-binding mRNA decay, CASM, apoptotic signaling) mechanistically relate to its conjugation chemistry and whether they share or bypass the lipidation cascade remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model unifying membrane and RNA-binding functions","Substrate determinants for protein ATG8ylation undefined","Crosstalk among transcriptional, translational, and ubiquitin-based regulation not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[1,15]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,4]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2,4,11]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,3,9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[13]}],"complexes":[],"partners":["ATG4B","ATG7","ATG3","VHL","HDAC6","SQSTM1","PGRMC1","BAG3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZQ8","full_name":"Microtubule-associated protein 1 light chain 3 beta","aliases":["Autophagy-related protein LC3 B","Autophagy-related ubiquitin-like modifier LC3 B","MAP1 light chain 3-like protein 2","Microtubule-associated proteins 1A/1B light chain 3B","MAP1A/MAP1B LC3 B","MAP1A/MAP1B light chain 3 B"],"length_aa":125,"mass_kda":14.7,"function":"Ubiquitin-like modifier involved in formation of autophagosomal vacuoles (autophagosomes) (PubMed:20418806, PubMed:23209295, PubMed:28017329). Plays a role in mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production (PubMed:23209295, PubMed:28017329). In response to cellular stress and upon mitochondria fission, binds C-18 ceramides and anchors autophagolysosomes to outer mitochondrial membranes to eliminate damaged mitochondria (PubMed:22922758). While LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation (PubMed:20418806, PubMed:23209295, PubMed:28017329). Promotes primary ciliogenesis by removing OFD1 from centriolar satellites via the autophagic pathway (PubMed:24089205). Through its interaction with the reticulophagy receptor TEX264, participates in the remodeling of subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover (PubMed:31006537, PubMed:31006538). Upon nutrient stress, directly recruits cofactor JMY to the phagophore membrane surfaces and promotes JMY's actin nucleation activity and autophagosome biogenesis during autophagy (PubMed:30420355)","subcellular_location":"Cytoplasmic vesicle, autophagosome membrane; Endomembrane system; Mitochondrion membrane; Cytoplasm, cytoskeleton; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q9GZQ8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP1LC3B","classification":"Not Classified","n_dependent_lines":168,"n_total_lines":1090,"dependency_fraction":0.15412844036697249},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000140941","cell_line_id":"CID000362","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"cytoskeleton","grade":2}],"interactors":[{"gene":"MAP1LC3B;MAP1LC3B2;MAP1LC3A","stoichiometry":10.0},{"gene":"MAP1B","stoichiometry":4.0},{"gene":"ATG3","stoichiometry":4.0},{"gene":"FYCO1","stoichiometry":4.0},{"gene":"MAP1A","stoichiometry":0.2},{"gene":"STK4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000362","total_profiled":1310},"omim":[{"mim_id":"621024","title":"PROTEIN PRENYLTRANSFERASE ALPHA SUBUNIT REPEAT-CONTAINING PROTEIN 1; PTAR1","url":"https://www.omim.org/entry/621024"},{"mim_id":"620673","title":"MICROTUBULE-ASSOCIATED PROTEIN 1, LIGHT CHAIN 3, BETA-2; MAP1LC3B2","url":"https://www.omim.org/entry/620673"},{"mim_id":"620608","title":"TESTIS-EXPRESSED GENE 264; TEX264","url":"https://www.omim.org/entry/620608"},{"mim_id":"618616","title":"MITOGEN-ACTIVATED PROTEIN KINASE 15; MAPK15","url":"https://www.omim.org/entry/618616"},{"mim_id":"617074","title":"SMITH-MAGENIS SYNDROME CHROMOSOME REGION, CANDIDATE GENE 8; SMCR8","url":"https://www.omim.org/entry/617074"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAP1LC3B"},"hgnc":{"alias_symbol":["ATG8F"],"prev_symbol":[]},"alphafold":{"accession":"Q9GZQ8","domains":[{"cath_id":"3.10.20.90","chopping":"6-123","consensus_level":"high","plddt":92.9026,"start":6,"end":123}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZQ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZQ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZQ8-F1-predicted_aligned_error_v6.png","plddt_mean":91.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP1LC3B","jax_strain_url":"https://www.jax.org/strain/search?query=MAP1LC3B"},"sequence":{"accession":"Q9GZQ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZQ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZQ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZQ8"}},"corpus_meta":[{"pmid":"20038797","id":"PMC_20038797","title":"The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5.","date":"2009","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/20038797","citation_count":682,"is_preprint":false},{"pmid":"12740394","id":"PMC_12740394","title":"Post-translational modifications of three members of the human MAP1LC3 family and detection of a novel type of modification for MAP1LC3B.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12740394","citation_count":247,"is_preprint":false},{"pmid":"15355958","id":"PMC_15355958","title":"Human light chain 3/MAP1LC3B is cleaved at its carboxyl-terminal Met121 to expose Gly120 for lipidation and targeting to autophagosomal membranes.","date":"2004","source":"The Journal of biological 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All three isoforms associate with autophagosomal membranes as shown by subcellular fractionation and immunofluorescence.\",\n      \"method\": \"Cell fractionation, immunofluorescence, biochemical characterization of post-translational modifications\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, immunofluorescence, biochemical modification mapping) in a single study; later contradicted/refined by PMID:15355958\",\n      \"pmids\": [\"12740394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The C-terminal Met-121 of MAP1LC3B is cleaved by human Atg4B to expose Gly-120, which is essential for subsequent ubiquitylation-like reactions: formation of Atg7-MAP1LC3B (E1-like) and Atg3-MAP1LC3B (E2-like) intermediates, and conjugation to phospholipid (PE). Gly-120 is required for both C-terminal cleavage and lipidation. RNA interference of MAP1LC3B mRNA decreased both endogenous MAP1LC3B-PL and total MAP1LC3B protein.\",\n      \"method\": \"In vitro cleavage assay with recombinant Atg4B, site-directed mutagenesis (G120A mutant), RNAi knockdown, cell fractionation, immunoprecipitation of enzyme-substrate intermediates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis, multiple orthogonal methods (in vitro assay, mutagenesis, RNAi, fractionation) in a single rigorous study\",\n      \"pmids\": [\"15355958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Hypoxia increases transcription of MAP1LC3B through the transcription factor ATF4, which is regulated by the PERK arm of the UPR. This transcriptional induction replenishes MAP1LC3B protein consumed during extensive autophagy. Cells deficient in PERK signaling fail to induce MAP1LC3B transcription and become depleted of MAP1LC3B protein during hypoxia.\",\n      \"method\": \"Transcriptional reporter assays, western blotting, PERK-deficient cell lines, human tumor xenografts with immunostaining\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines and in vivo xenograft model, but mechanism inferred from loss-of-function (PERK KO) and expression measurements without direct promoter binding demonstrated for MAP1LC3B\",\n      \"pmids\": [\"20038797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HCV core protein activates autophagy through UPR pathways: DDIT3/CHOP directly binds to the -253 to -99 base region of the MAP1LC3B promoter to upregulate its transcription. The EIF2AK3/ATF4 pathway upregulates ATG12 but not MAP1LC3B.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation/promoter binding assay, western blotting, qPCR in Huh7 cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated and reporter assay performed, single lab\",\n      \"pmids\": [\"24589849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PGRMC1/S2R (progesterone receptor membrane component 1) physically associates with MAP1LC3 and UVRAG. PGRMC1 is required for autophagy-dependent degradation of ubiquitinated proteins and damaged organelles; its inhibition by RNAi or small molecules causes accumulation of autophagy substrates and aberrant mitochondria.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, small-molecule inhibition, western blotting for autophagy substrates\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional RNAi with substrate accumulation readout, single lab, two orthogonal approaches\",\n      \"pmids\": [\"24113030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The cochaperone BAG3 controls the basal amount of MAP1LC3B protein by regulating translation of its mRNA, not its transcription. BAG3 knockdown reduced total LC3B protein without affecting LC3B mRNA levels or LC3B lipidation induced by starvation or proteasome inhibition. This effect appeared specific to LC3B among ATG proteins tested.\",\n      \"method\": \"RNAi knockdown, western blotting, RT-qPCR, polysome profiling/translational analysis in HeLa and HEK293 cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (transcriptional vs. translational assays, knockdown), single lab\",\n      \"pmids\": [\"26654586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"pVHL (Von Hippel-Lindau protein) interacts with MAP1LC3B via an LIR motif in its beta domain and ubiquitinates MAP1LC3B, thereby inhibiting LC3B-mediated autophagy. The L101A VHL mutant fails to interact with MAP1LC3B and fails to induce its ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (L101A), western blotting in VHL-deficient and VHL-expressing RCC cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis validation and functional ubiquitination assay, single lab\",\n      \"pmids\": [\"30902965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAP1LC3B deficiency in mice leads to failure to upregulate autophagosome formation in dendritic cells upon RSV infection, resulting in IL-1β and IL-6 secretion and enhanced IL-17a-dependent lung pathology. Both hematopoietic and structural cell LC3B deficiency contribute to this phenotype, as shown by bone marrow chimeras.\",\n      \"method\": \"LC3b knockout mice, bone marrow chimeras, RSV infection model, cytokine measurements, in vitro DC assays\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with bone marrow chimera epistasis and defined cytokine phenotype, single lab\",\n      \"pmids\": [\"25669150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LC3B knockout mice show susceptibility to bleomycin-induced lung injury and fibrosis. LC3B knockdown sensitizes lung epithelial cells to bleomycin-induced apoptosis while its overexpression is protective. Cathepsin A was identified as a novel LC3B-binding partner; its overexpression drives lung epithelial cell apoptosis and it accumulates in aged LC3B-/- mice and IPF patient lungs.\",\n      \"method\": \"LC3B knockout mice, bleomycin lung fibrosis model, RNAi knockdown and overexpression in MLE12 cells, co-immunoprecipitation (cathepsin A binding), electron microscopy, proteasomal activity assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo phenotype, Co-IP for novel binding partner, in vitro functional overexpression/knockdown, single lab\",\n      \"pmids\": [\"31431059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAP1LC3B has a non-autophagic function upstream of procaspase-8 cleavage that contributes to ER stress-induced apoptosis triggered by thapsigargin. ATF4 and CHOP independently regulate MAP1LC3B protein upregulation in this context, and this function is required for optimal cytotoxicity in prostate and colon cancer cells.\",\n      \"method\": \"RNAi knockdown, western blotting, caspase activity assays, propidium iodide staining for cell death, real-time RT-PCR in LNCaP and HCT116 cells\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with defined apoptotic phenotype in two cell lines, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31987044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC6 physically interacts with MAP1LC3B and mediates its monoubiquitination, reducing MAP1LC3B protein levels and impairing autophagy. This promotes pathological cardiac hypertrophy. HDAC6 inhibition restores MAP1LC3B expression and autophagy, attenuating ISO-induced cardiac hypertrophy in mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, HDAC6 overexpression and inhibition, ISO-induced cardiac hypertrophy mouse model, western blotting\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination assay and in vivo rescue experiment, single lab\",\n      \"pmids\": [\"40212005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ectopic expression of SQSTM1 and its MAP1LC3B-binding domain (LIR domain) targeted to the mitochondrial outer membrane directly induces mitophagy (forced mitophagy), capable of degrading approximately half of mitochondria and their DNA in HeLa cells and mouse embryos without apparent effects on mitochondrial membrane potential, ROS, mitosis, or embryo development.\",\n      \"method\": \"Ectopic expression of mitochondria-targeted SQSTM1 LIR domain, flow cytometry, fluorescence microscopy, mitochondrial DNA quantification in HeLa cells and mouse embryos\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in cells and embryos with domain-level resolution, single lab\",\n      \"pmids\": [\"35574946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"m6A RNA methylation of Map1lc3b mRNA, mediated by METTL3 (writer) and ALKBH5 (eraser), suppresses autophagic processes in Leydig cells exposed to BPA. Integrated transcriptomic and MeRIP-seq analysis identified Map1lc3b mRNA as a specific target of upregulated m6A modification induced by BPA.\",\n      \"method\": \"MeRIP-seq, RNA-seq integration, METTL3/ALKBH5 manipulation, in vivo and in vitro BPA exposure models, western blotting\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq with writer/eraser genetic manipulation and functional readout, single lab\",\n      \"pmids\": [\"39662354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAP1LC3B functions as an RNA-binding protein in early embryos and mediates maternal mRNA decay during the maternal-to-zygotic transition (MZT). LC3B-mediated mRNA decay operates with faster kinetics than the classical BTG4-CCR4-NOT pathway. Knockdown of LC3B or autophagy inhibition delays maternal mRNA clearance, impairs zygotic genome activation, and causes developmental arrest. Maternal Suv39h2 mRNA was identified as a key LC3B target.\",\n      \"method\": \"RIP-seq, RNA-seq, CUT&Tag in early embryos, LC3B knockdown, autophagy inhibition, developmental assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genomic and functional methods (RIP-seq, RNA-seq, CUT&Tag, knockdown with developmental phenotype), single lab\",\n      \"pmids\": [\"41231099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IMP1 (IGF2BP1) colocalization with MAP1LC3B transcripts at homeostasis is reduced under stress. IMP1 deletion or mutation of IMP1 phosphorylation sites enhances MAP1LC3B expression at the protein level, promoting autophagy and intestinal stem cell regeneration.\",\n      \"method\": \"Single-molecule FISH, immunofluorescence, IMP1 knockout and phosphorylation-site mutant studies, organoid formation assay, in vivo irradiation regeneration model\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-molecule FISH colocalization with genetic and functional validation, single lab\",\n      \"pmids\": [\"38081361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Protein ATG8ylation of MAP1LC3B (covalent conjugation to cellular proteins rather than lipids) requires E1-like ATG7 and E2-like ATG3, in common with lipid ATG8ylation, but is independent of the E3-like ATG12-ATG5-ATG16L1 complex (ATG5 knockout cells can still form ATG8ylated protein conjugates). ATG7 itself is identified as a target of MAP1LC3B ATG8ylation.\",\n      \"method\": \"CRISPR/Cas9 knockout cell lines (ATG5, ATG7, ATG3), deconjugation-resistant MAP1LC3B mutant (Q116P G120), western blotting, immunoprecipitation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with reconstitution-level mechanistic dissection, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.07.03.601942\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAP1LC3B undergoes CASM (conjugation of ATG8 to single membranes) at the Golgi apparatus in TRIM46-deficient cells. This non-degradative Golgi Atg8ylation mechanistically resembles CASM. Genetic inhibition of CASM in TRIM46-deficient cells exacerbates Golgi morphology defects, and knockdown of CASM genes impairs Golgi reformation after drug-induced fragmentation, demonstrating that CASM contributes to Golgi repair.\",\n      \"method\": \"TRIM46 knockout cells, CASM gene knockdown, immunofluorescence colocalization (LC3B/GABARAP with TGOLN2), drug-induced Golgi fragmentation assay, TFEB activation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, preprint, colocalization and knockdown with morphological readout, no biochemical reconstitution\",\n      \"pmids\": [\"bio_10.1101_2025.09.04.674289\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MAP1LC3B is a ubiquitin-like autophagy protein that is processed by Atg4B-mediated cleavage of its C-terminal Met-121 to expose Gly-120, which is then conjugated to phosphatidylethanolamine via Atg7 (E1) and Atg3 (E2) to form the lipidated LC3B-II form that associates with autophagosomal membranes; its transcription is induced by ATF4/CHOP downstream of the PERK-UPR arm, its translation is regulated by BAG3, and its protein stability is modulated by ubiquitination via HDAC6 and pVHL; beyond canonical autophagy, MAP1LC3B functions as an RNA-binding protein mediating maternal mRNA decay, participates in non-degradative CASM at endomembranes, and has non-autophagic roles in ER stress-induced apoptosis upstream of caspase-8.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAP1LC3B is a ubiquitin-like protein central to autophagosome biogenesis that is matured through a conjugation cascade: human Atg4B cleaves its C-terminal Met-121 to expose Gly-120, which is then activated by the E1-like Atg7 and transferred via the E2-like Atg3 for conjugation to phospholipid (PE), generating the membrane-associated lipidated form essential for autophagy [#1]. Gly-120 is strictly required for both cleavage and lipidation [#1], and the protein associates with autophagosomal membranes [#0]. Its abundance is controlled at multiple levels: ATF4 (downstream of the PERK arm of the UPR) drives transcription that replenishes MAP1LC3B consumed during hypoxic autophagy [#2], CHOP/DDIT3 directly binds the MAP1LC3B promoter to upregulate transcription [#3], the cochaperone BAG3 selectively controls its translation [#5], and protein stability is restrained by LIR-dependent ubiquitination via pVHL [#6] and monoubiquitination via HDAC6, which impairs autophagy and promotes cardiac hypertrophy [#10]. The protein engages substrate-recruiting partners through LIR motifs, including SQSTM1, whose mitochondria-targeted LIR domain is sufficient to force mitophagy [#11], and PGRMC1, required for autophagic clearance of ubiquitinated proteins and damaged organelles [#4]. Beyond canonical degradative autophagy, MAP1LC3B acts upstream of procaspase-8 cleavage in ER stress-induced apoptosis [#9], functions as an RNA-binding protein mediating rapid maternal mRNA decay during the maternal-to-zygotic transition [#13], and can be covalently conjugated to proteins (ATG8ylation) via Atg7/Atg3 independently of the ATG12-ATG5-ATG16L1 complex [#15]. Genetic loss in mice causes defects in dendritic-cell autophagy with exaggerated IL-17a-dependent lung pathology during RSV infection [#7] and sensitizes lung epithelium to bleomycin-induced fibrosis [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that MAP1LC3B is post-translationally modified and membrane-associated, distinguishing it biochemically from its paralogs and placing it on autophagosomal membranes.\",\n      \"evidence\": \"Cell fractionation, immunofluorescence, and biochemical modification mapping of three LC3 isoforms\",\n      \"pmids\": [\"12740394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Initial claim of Lys-122 modification without C-terminal cleavage was refined by later reconstitution work\", \"Enzymes mediating the modification not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the core conjugation mechanism: Atg4B cleavage at Gly-120 licenses Atg7/Atg3-dependent lipidation to PE, answering how LC3B becomes membrane-competent.\",\n      \"evidence\": \"In vitro cleavage with recombinant Atg4B, G120A mutagenesis, RNAi, fractionation, and enzyme-substrate intermediate IP\",\n      \"pmids\": [\"15355958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address upstream membrane-targeting specificity\", \"Regulation of the cascade in vivo not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that LC3B protein pools are transcriptionally replenished via PERK/ATF4 signaling during hypoxic autophagy, linking the UPR to autophagy capacity.\",\n      \"evidence\": \"Reporter assays, western blotting, PERK-deficient cells, and tumor xenografts\",\n      \"pmids\": [\"20038797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ATF4 binding to the MAP1LC3B promoter not demonstrated\", \"Relative contribution of transcription vs. conjugation to autophagy output unquantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified CHOP/DDIT3 as a direct transcriptional activator binding the MAP1LC3B promoter, distinguishing it from the ATF4 arm which acts on ATG12.\",\n      \"evidence\": \"Luciferase reporter, ChIP/promoter binding, qPCR, and western blotting in HCV-infected Huh7 cells\",\n      \"pmids\": [\"24589849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cooperativity between CHOP and ATF4 inputs not dissected\", \"Context-dependence beyond HCV infection unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a translational control layer in which BAG3 selectively sets basal LC3B protein levels without affecting transcription or lipidation.\",\n      \"evidence\": \"RNAi, RT-qPCR, western blotting, and polysome profiling in HeLa and HEK293 cells\",\n      \"pmids\": [\"26654586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which BAG3 engages LC3B mRNA not defined\", \"Specificity for LC3B among ATG mRNAs not fully mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected LC3B to substrate clearance through PGRMC1, which physically associates with it and is required for autophagic degradation of ubiquitinated proteins and damaged organelles.\",\n      \"evidence\": \"Co-IP, RNAi, small-molecule inhibition, and autophagy substrate readouts\",\n      \"pmids\": [\"24113030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of the LC3-PGRMC1 association unresolved\", \"No reciprocal validation or structural basis\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established LIR-dependent ubiquitination of LC3B by pVHL as a negative regulator of LC3B-mediated autophagy.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and L101A mutagenesis in RCC cell lines\",\n      \"pmids\": [\"30902965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain topology and fate of ubiquitinated LC3B unspecified\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified HDAC6-mediated monoubiquitination as a second ubiquitin-dependent route lowering LC3B levels, with pathological cardiac hypertrophy as the in vivo consequence.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, HDAC6 overexpression/inhibition, and ISO-induced cardiac hypertrophy mouse model\",\n      \"pmids\": [\"40212005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HDAC6 acts as the ligase or a scaffold not clarified\", \"Relationship to pVHL-mediated ubiquitination not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo that LC3B is required for dendritic-cell autophagy that restrains IL-17a-dependent lung immunopathology during RSV infection.\",\n      \"evidence\": \"LC3b knockout mice, bone marrow chimeras, RSV infection, and cytokine measurements\",\n      \"pmids\": [\"25669150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which autophagy substrates suppress inflammation unidentified\", \"Mechanism linking LC3B loss to cytokine output undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed LC3B is protective against bleomycin lung injury and identified cathepsin A as a binding partner whose accumulation drives epithelial apoptosis.\",\n      \"evidence\": \"LC3B knockout mice, bleomycin model, knockdown/overexpression in MLE12 cells, Co-IP, and EM\",\n      \"pmids\": [\"31431059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cathepsin A is an autophagic degradation substrate of LC3B not established\", \"Direct vs. indirect binding not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a non-autophagic role for LC3B acting upstream of procaspase-8 cleavage in ER stress-induced apoptosis, regulated by ATF4 and CHOP.\",\n      \"evidence\": \"RNAi, caspase activity assays, PI staining, and RT-PCR in LNCaP and HCT116 cells\",\n      \"pmids\": [\"31987044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between LC3B and procaspase-8 activation not mapped\", \"Whether lipidation is required for this function unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that the LC3B-binding LIR domain of SQSTM1, when targeted to mitochondria, is sufficient to force mitophagy, establishing LIR-LC3B engagement as a deployable cargo-targeting module.\",\n      \"evidence\": \"Mitochondria-targeted SQSTM1 LIR expression, flow cytometry, microscopy, and mtDNA quantification in HeLa cells and mouse embryos\",\n      \"pmids\": [\"35574946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Requirement for endogenous receptor selectivity bypassed by forced system\", \"Generalizability to other organelles not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that m6A methylation of Map1lc3b mRNA by METTL3/ALKBH5 suppresses autophagy, adding an epitranscriptomic regulatory layer.\",\n      \"evidence\": \"MeRIP-seq, RNA-seq integration, writer/eraser manipulation, and BPA exposure models\",\n      \"pmids\": [\"39662354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which reader proteins act on methylated Map1lc3b mRNA unidentified\", \"Effect on translation vs. stability not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established protein ATG8ylation of LC3B as a conjugation activity requiring Atg7/Atg3 but independent of the ATG12-ATG5-ATG16L1 complex, with ATG7 itself as a conjugation target.\",\n      \"evidence\": \"CRISPR ATG5/ATG7/ATG3 knockouts, deconjugation-resistant mutant, western blotting, and IP (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.03.601942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of protein ATG8ylation not defined\", \"Peer review pending; broader substrate range unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified LC3B as an RNA-binding protein driving rapid maternal mRNA decay during the maternal-to-zygotic transition, a function distinct from membrane autophagy.\",\n      \"evidence\": \"RIP-seq, RNA-seq, CUT&Tag, LC3B knockdown, and developmental assays in early embryos\",\n      \"pmids\": [\"41231099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of LC3B RNA binding undefined\", \"Whether decay requires lipidation or the conjugation machinery unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed that LC3B undergoes CASM at the Golgi to support Golgi repair in TRIM46-deficient cells, extending non-degradative ATG8ylation to organelle maintenance.\",\n      \"evidence\": \"TRIM46 knockout cells, CASM gene knockdown, colocalization, and Golgi fragmentation assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.04.674289\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No biochemical reconstitution; colocalization-based\", \"Single lab, preprint not peer-reviewed\", \"Direct role of LC3B vs. GABARAP at the Golgi not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LC3B's diverse non-canonical activities (RNA-binding mRNA decay, CASM, apoptotic signaling) mechanistically relate to its conjugation chemistry and whether they share or bypass the lipidation cascade remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model unifying membrane and RNA-binding functions\", \"Substrate determinants for protein ATG8ylation undefined\", \"Crosstalk among transcriptional, translational, and ubiquitin-based regulation not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [1, 15]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005776\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2, 4, 11]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATG4B\", \"ATG7\", \"ATG3\", \"VHL\", \"HDAC6\", \"SQSTM1\", \"PGRMC1\", \"BAG3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}