{"gene":"MAP1LC3C","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2003,"finding":"MAP1LC3C undergoes C-terminal proteolytic cleavage after the conserved Gly residue (unlike MAP1LC3B), and the processed form is associated with autophagosome membranes, as determined by cell fractionation and immunofluorescence.","method":"Cell fractionation, immunofluorescence, post-translational modification analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell fractionation and immunofluorescence with comparison across isoforms; single lab but two orthogonal methods","pmids":["12740394"],"is_preprint":false},{"year":2013,"finding":"Arg68 is an essential residue facilitating interaction between ATG8 family proteins (including MAP1LC3C) and ATG4B via a salt bridge with Asp171 of ATG4B, required for C-terminal cleavage and autophagosome formation.","method":"Structural simulation, mutagenesis, autophagic flux assay","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — structural modeling plus mutagenesis with functional readout; single lab","pmids":["23721406"],"is_preprint":false},{"year":2019,"finding":"MAP1LC3C has a unique N-terminal 'sticky arm' consisting of a polyproline II motif on a flexible linker (rather than stable helix α1 found in other LC3/GABARAP proteins), and Ser18 at the linker-core interface can be phosphorylated in vitro by protein kinase A, causing conformational changes including alterations at the LIR-binding interface.","method":"NMR spectroscopy, molecular dynamics simulations, in vitro kinase assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution NMR structure with functional validation by in vitro phosphorylation and MD simulations; multiple orthogonal methods in a single rigorous study","pmids":["31578424"],"is_preprint":false},{"year":2019,"finding":"MAP1LC3C forms a complex with the MET/HGF receptor tyrosine kinase and mediates selective autophagic degradation of HGF-activated, internalized MET; LC3C deletion abrogates Met entry into the autophagy-dependent degradative pathway, enhancing Met signaling and cell invasion.","method":"Co-immunoprecipitation, genetic deletion (LC3C KO), cell invasion assays, immunofluorescence","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — complex formation by Co-IP, genetic loss-of-function with specific phenotypic readout, domain rescue experiments; single lab with multiple orthogonal methods","pmids":["31851933"],"is_preprint":false},{"year":2020,"finding":"MAP1LC3C physically interacts with CALCOCO1, and genetic deletion of CALCOCO1 disrupts reticulophagy (selective autophagy of the endoplasmic reticulum), placing CALCOCO1-LC3C interaction in MTOR-regulated selective autophagy.","method":"Co-immunoprecipitation (mass spectrometry proteomics + direct interaction), genetic KO, reticulophagy assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus direct interaction validated, genetic KO with defined autophagy phenotype; single lab","pmids":["31971854"],"is_preprint":false},{"year":2021,"finding":"LC3C autophagy requires a noncanonical upstream regulatory complex including ULK3, UVRAG, RUBCN, PIK3C2A, and TSG101 (an ESCRT member), distinct from canonical autophagy regulators; postdivision midbody rings (PDMBs) are direct targets of LC3C-dependent selective degradation, and the LC3C C-terminal 20-amino acid peptide (cleaved during Gly126 lipidation) is necessary and sufficient for PDMB degradation.","method":"Genetic knockdown/knockout, autophagy flux assays, domain truncation/rescue experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations with defined mechanistic outputs, domain-sufficiency experiments; single lab with multiple orthogonal approaches","pmids":["33988680"],"is_preprint":false},{"year":2022,"finding":"LC3C interacts with cardiolipin (CL)-containing membranes in vitro but its colocalization with mitochondria is not rotenone-dependent, and loss of LC3C does not decrease CCCP-induced mitophagy, indicating LC3C does not participate in cargo recognition during CL-mediated mitophagy (negative finding).","method":"In vitro lipid-binding assays with model membranes, fluorescence colocalization in SH-SY5Y cells, siRNA knockdown with CCCP/rotenone-induced mitophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus cell-based colocalization plus functional mitophagy assay; single lab with multiple orthogonal methods; findings are explicitly negative for LC3C in mitophagy","pmids":["35414338"],"is_preprint":false},{"year":2023,"finding":"Loss of LC3C leads to peripheral positioning of lysosomes and lysosomal exocytosis (LE) independently of LC3C's autophagic activity; this LE is accompanied by transcriptomic reprogramming with altered zinc-related gene expression, decreased intracellular zinc, altered polycomb repressor complex 2 activity, and increased tumor initiation properties in xenograft models.","method":"Isogenic cell lines with LC3C loss, immunocytochemistry, metabolomics, transcriptomics, xenograft tumor assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary cellular and molecular methods; single lab, defined mechanistic dissection of autophagic vs. non-autophagic LC3C function","pmids":["37003503"],"is_preprint":false},{"year":2021,"finding":"TFG (TRK-fused gene) facilitates ULK1-MAP1LC3C interaction to modulate omegasome and autophagosome formation under starvation conditions.","method":"Co-immunoprecipitation, autophagosome/omegasome formation assays (referenced from primary study)","journal":"Molecular & cellular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single commentary describing findings from primary study; abstract provides limited methodological detail; single lab","pmids":["34616872"],"is_preprint":false},{"year":2020,"finding":"MAP1LC3C plays a role in odontogenic differentiation of human dental pulp cells (DPCs): MAP1LC3C expression is selectively upregulated during odontogenic differentiation and shRNA knockdown of MAP1LC3C causes strong downregulation of odontogenic markers (DMP1 and DSPP), while knockdown of MAP1LC3B has lesser effect.","method":"shRNA knockdown, RT-qPCR, marker protein detection during odontogenic differentiation","journal":"Tissue engineering and regenerative medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — selective knockdown with specific differentiation marker readout, comparative with LC3B isoform; single lab, multiple markers","pmids":["33230801"],"is_preprint":false},{"year":2025,"finding":"Silencing MAP1LC3C in tumor cells inhibits CIITA expression and suppresses HLA class II production, linking LC3C to antigen presentation machinery regulation.","method":"siRNA/shRNA silencing of MAP1LC3C, Western blot/RT-qPCR for CIITA and HLA class II","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, no reconstitution or direct interaction experiments described","pmids":["39928678"],"is_preprint":false},{"year":2026,"finding":"Non-phosphorylated (Thr308-dephosphorylated) AKT1 acts as a scaffold to recruit SQSTM1, enabling PDPK1-dependent phosphorylation of SQSTM1 at Ser349 and selective loading of viral capsids into LC3C-positive phagophores for antiviral degradation.","method":"Genetic KO, phospho-mutant expression, co-immunoprecipitation, in vivo viral replication assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations (KO, phospho-mutant), biochemical interaction assays, in vivo validation; single lab","pmids":["42152503"],"is_preprint":false}],"current_model":"MAP1LC3C (LC3C) is a human-specific ATG8 family member that undergoes ATG4B-mediated C-terminal cleavage (requiring an Arg68–Asp171 salt bridge) followed by PE conjugation for autophagosome membrane association; it possesses a unique N-terminal polyproline II 'sticky arm' that can be phosphorylated at Ser18 by PKA to modulate LIR-binding surface conformation; it mediates selective autophagy through a noncanonical regulatory complex (ULK3/UVRAG/RUBCN/PIK3C2A/TSG101) using its C-terminal peptide to target postdivision midbody rings, interacts with CALCOCO1 for reticulophagy and with MET RTK for receptor degradation, and independently of autophagy controls lysosomal positioning and exocytosis to regulate intracellular zinc levels and tumor-suppressive functions."},"narrative":{"mechanistic_narrative":"MAP1LC3C (LC3C) is an ATG8-family ubiquitin-like protein that drives selective autophagy and, independently, governs lysosomal positioning to exert tumor-suppressive functions [PMID:31851933, PMID:37003503]. Like other ATG8 proteins, it is processed at its conserved C-terminal Gly residue and recruited to autophagosome membranes [PMID:12740394]; this cleavage depends on a salt bridge between LC3C Arg68 and Asp171 of the cysteine protease ATG4B, which is required for downstream lipidation and autophagosome formation [PMID:23721406]. LC3C is structurally distinguished by a unique N-terminal polyproline II 'sticky arm' on a flexible linker in place of the stable α1 helix of other LC3/GABARAP proteins, and phosphorylation of Ser18 at the linker-core interface by PKA remodels its LIR-binding surface [PMID:31578424]. Through this surface and adaptor interactions, LC3C executes cargo-selective degradation: it complexes with the MET/HGF receptor tyrosine kinase to route activated, internalized MET into autophagic degradation and restrain MET signaling and cell invasion [PMID:31851933], binds CALCOCO1 to mediate reticulophagy [PMID:31971854], and uses a noncanonical upstream complex (ULK3, UVRAG, RUBCN, PIK3C2A, TSG101) together with its cleaved C-terminal 20-residue peptide to target postdivision midbody rings [PMID:33988680]. Independently of its autophagic activity, loss of LC3C drives peripheral lysosome positioning and lysosomal exocytosis, lowering intracellular zinc, reprogramming the transcriptome, and increasing tumor-initiating capacity [PMID:37003503]. LC3C does not participate in cardiolipin-mediated mitophagy [PMID:35414338].","teleology":[{"year":2003,"claim":"Establishing that LC3C, despite divergence from LC3B, behaves as a membrane-conjugating ATG8 protein answered whether this isoform is competent for the canonical autophagy lipidation cycle.","evidence":"Cell fractionation and immunofluorescence showing C-terminal cleavage after the conserved Gly and autophagosome membrane association","pmids":["12740394"],"confidence":"Medium","gaps":["The protease responsible for cleavage was not identified","Functional consequences and selectivity of LC3C autophagy were not addressed"]},{"year":2013,"claim":"Defining the LC3C Arg68–ATG4B Asp171 salt bridge explained the molecular requirement for C-terminal processing and connected LC3C to the ATG4B cleavage machinery.","evidence":"Structural simulation, mutagenesis, and autophagic flux assays across ATG8 family members","pmids":["23721406"],"confidence":"Medium","gaps":["Done by modeling plus mutagenesis without a co-crystal structure of LC3C-ATG4B","Did not establish isoform-specific differences in processing kinetics"]},{"year":2019,"claim":"Solving the unique N-terminal 'sticky arm' architecture and identifying Ser18 PKA phosphorylation revealed how LC3C's adaptor-binding surface can be conformationally regulated, distinguishing it from other LC3/GABARAP proteins.","evidence":"NMR spectroscopy, molecular dynamics simulations, and in vitro PKA kinase assay","pmids":["31578424"],"confidence":"High","gaps":["Ser18 phosphorylation shown in vitro; cellular kinase activity and physiological trigger not established","Functional effect on specific cargo selection not tested"]},{"year":2019,"claim":"Demonstrating LC3C-MET complex formation and LC3C-dependent MET degradation answered how a specific receptor tyrosine kinase is cleared by autophagy and linked LC3C to suppression of invasion.","evidence":"Co-immunoprecipitation, LC3C knockout, domain rescue, and cell invasion assays","pmids":["31851933"],"confidence":"High","gaps":["Direct vs. adaptor-bridged LC3C-MET binding not resolved","Single lab; in vivo relevance of MET clearance not established"]},{"year":2020,"claim":"Identifying the LC3C-CALCOCO1 interaction placed LC3C in MTOR-regulated reticulophagy, expanding its selective-autophagy cargo repertoire to the ER.","evidence":"Proteomic and direct interaction validation with CALCOCO1 KO and reticulophagy assays","pmids":["31971854"],"confidence":"Medium","gaps":["LC3C-specific contribution versus other ATG8 isoforms in reticulophagy not isolated","Structural basis of the LC3C-CALCOCO1 LIR interaction not defined"]},{"year":2020,"claim":"Linking LC3C expression to odontogenic differentiation suggested a tissue-specific developmental role beyond bulk autophagy, with isoform selectivity over LC3B.","evidence":"shRNA knockdown and RT-qPCR/protein readout of DMP1 and DSPP markers in human dental pulp cells","pmids":["33230801"],"confidence":"Medium","gaps":["Mechanism connecting LC3C to odontogenic gene expression unknown","Whether the effect depends on autophagy not tested"]},{"year":2021,"claim":"Defining a noncanonical upstream regulatory complex and the cleaved C-terminal peptide as the targeting determinant for postdivision midbody rings established that LC3C-driven selective autophagy uses dedicated machinery distinct from canonical autophagy.","evidence":"Genetic knockdown/knockout, autophagic flux assays, and domain truncation/sufficiency experiments","pmids":["33988680"],"confidence":"High","gaps":["How the ULK3/UVRAG/RUBCN/PIK3C2A/TSG101 components are assembled and ordered not resolved","Direct binding partner of the C-terminal 20-aa peptide on PDMBs not identified"]},{"year":2021,"claim":"Reporting that TFG facilitates ULK1-LC3C interaction proposed a bridging factor for omegasome/autophagosome formation under starvation.","evidence":"Co-immunoprecipitation and autophagosome/omegasome formation assays described in a commentary","pmids":["34616872"],"confidence":"Low","gaps":["Low-confidence commentary with limited methodological detail; not independently confirmed","Direct vs. indirect TFG-LC3C-ULK1 connectivity unclear"]},{"year":2022,"claim":"Testing LC3C in cardiolipin-mediated mitophagy answered whether its lipid-binding extends to mitochondrial cargo recognition, with a clear negative result.","evidence":"In vitro cardiolipin membrane binding, colocalization in SH-SY5Y cells, and siRNA with CCCP/rotenone mitophagy assays","pmids":["35414338"],"confidence":"Medium","gaps":["Does not exclude LC3C roles in other forms of mitophagy","In vitro CL binding without an identified physiological function"]},{"year":2023,"claim":"Separating LC3C's autophagy-dependent and -independent functions revealed an autophagy-independent control of lysosomal positioning and exocytosis that regulates zinc and tumor initiation.","evidence":"Isogenic LC3C-loss cell lines, immunocytochemistry, metabolomics, transcriptomics, and xenograft tumor assays","pmids":["37003503"],"confidence":"Medium","gaps":["Molecular mechanism by which LC3C controls lysosome positioning not defined","Causal chain from zinc changes to PRC2 activity and tumor initiation incompletely mapped"]},{"year":2025,"claim":"Connecting LC3C silencing to reduced CIITA and HLA class II proposed a role in antigen-presentation machinery regulation in tumor cells.","evidence":"siRNA/shRNA silencing with CIITA and HLA class II readout by Western blot/RT-qPCR","pmids":["39928678"],"confidence":"Low","gaps":["Low-confidence; no direct interaction or reconstitution experiments","Mechanism linking LC3C to CIITA transcription unknown"]},{"year":2026,"claim":"Defining an AKT1-scaffold/PDPK1/SQSTM1 axis that loads viral capsids into LC3C-positive phagophores established LC3C participation in antiviral selective autophagy.","evidence":"Genetic KO, phospho-mutant expression, co-immunoprecipitation, and in vivo viral replication assays","pmids":["42152503"],"confidence":"Medium","gaps":["Direct LC3C-SQSTM1 engagement during capsid loading not fully resolved","Generalizability across virus families not established"]},{"year":null,"claim":"How LC3C selects among its diverse cargoes (MET, ER, midbody rings, viral capsids) and how its Ser18 phosphorylation and unique 'sticky arm' tune adaptor choice in cells remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking sticky-arm conformation to cargo selectivity","Physiological kinases/phosphatases governing Ser18 in vivo unidentified","Molecular basis of the autophagy-independent lysosomal positioning function unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,3,5]}],"complexes":[],"partners":["ATG4B","MET","CALCOCO1","ULK3","UVRAG","RUBCN","PIK3C2A","TSG101"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXW4","full_name":"Microtubule-associated protein 1 light chain 3 gamma","aliases":["Autophagy-related protein LC3 C","Autophagy-related ubiquitin-like modifier LC3 C","MAP1 light chain 3-like protein 3","Microtubule-associated proteins 1A/1B light chain 3C","MAP1A/MAP1B LC3 C","MAP1A/MAP1B light chain 3 C"],"length_aa":147,"mass_kda":16.9,"function":"Ubiquitin-like modifier that plays a crucial role in antibacterial autophagy (xenophagy) through the selective binding of CALCOCO2 (PubMed:23022382). Recruits all ATG8 family members to infecting bacteria such as S.typhimurium (PubMed:23022382). May also play a role in aggrephagy, the macroautophagic degradation of ubiquitinated and aggregated proteins (PubMed:28404643)","subcellular_location":"Cytoplasmic vesicle, autophagosome membrane; Endomembrane system; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9BXW4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP1LC3C","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAP1LC3C","total_profiled":1310},"omim":[{"mim_id":"620673","title":"MICROTUBULE-ASSOCIATED PROTEIN 1, LIGHT CHAIN 3, BETA-2; MAP1LC3B2","url":"https://www.omim.org/entry/620673"},{"mim_id":"612433","title":"DEAFNESS, AUTOSOMAL RECESSIVE 45; DFNB45","url":"https://www.omim.org/entry/612433"},{"mim_id":"611338","title":"AUTOPHAGY-RELATED 4B CYSTEINE PEPTIDASE; ATG4B","url":"https://www.omim.org/entry/611338"},{"mim_id":"609605","title":"MICROTUBULE-ASSOCIATED PROTEIN 1, LIGHT CHAIN 3, GAMMA; MAP1LC3C","url":"https://www.omim.org/entry/609605"},{"mim_id":"609604","title":"MICROTUBULE-ASSOCIATED PROTEIN 1, LIGHT CHAIN 3, BETA; MAP1LC3B","url":"https://www.omim.org/entry/609604"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytoplasmic bodies","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":12.9},{"tissue":"breast","ntpm":13.2}],"url":"https://www.proteinatlas.org/search/MAP1LC3C"},"hgnc":{"alias_symbol":["ATG8J"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXW4","domains":[{"cath_id":"3.10.20.90","chopping":"14-126","consensus_level":"high","plddt":86.9914,"start":14,"end":126}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXW4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXW4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXW4-F1-predicted_aligned_error_v6.png","plddt_mean":79.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP1LC3C","jax_strain_url":"https://www.jax.org/strain/search?query=MAP1LC3C"},"sequence":{"accession":"Q9BXW4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXW4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXW4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXW4"}},"corpus_meta":[{"pmid":"12740394","id":"PMC_12740394","title":"Post-translational 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architecture.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/42115886","citation_count":0,"is_preprint":false},{"pmid":"41946072","id":"PMC_41946072","title":"Screening of M6a methylated genes associated with preovulatory follicle development in Bashang long-tailed chicken.","date":"2026","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/41946072","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20000,"output_tokens":2831,"usd":0.051233,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10179,"output_tokens":3964,"usd":0.074997,"stage2_stop_reason":"end_turn"},"total_usd":0.12623,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"MAP1LC3C undergoes C-terminal proteolytic cleavage after the conserved Gly residue (unlike MAP1LC3B), and the processed form is associated with autophagosome membranes, as determined by cell fractionation and immunofluorescence.\",\n      \"method\": \"Cell fractionation, immunofluorescence, post-translational modification analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell fractionation and immunofluorescence with comparison across isoforms; single lab but two orthogonal methods\",\n      \"pmids\": [\"12740394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Arg68 is an essential residue facilitating interaction between ATG8 family proteins (including MAP1LC3C) and ATG4B via a salt bridge with Asp171 of ATG4B, required for C-terminal cleavage and autophagosome formation.\",\n      \"method\": \"Structural simulation, mutagenesis, autophagic flux assay\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural modeling plus mutagenesis with functional readout; single lab\",\n      \"pmids\": [\"23721406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAP1LC3C has a unique N-terminal 'sticky arm' consisting of a polyproline II motif on a flexible linker (rather than stable helix α1 found in other LC3/GABARAP proteins), and Ser18 at the linker-core interface can be phosphorylated in vitro by protein kinase A, causing conformational changes including alterations at the LIR-binding interface.\",\n      \"method\": \"NMR spectroscopy, molecular dynamics simulations, in vitro kinase assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution NMR structure with functional validation by in vitro phosphorylation and MD simulations; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31578424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAP1LC3C forms a complex with the MET/HGF receptor tyrosine kinase and mediates selective autophagic degradation of HGF-activated, internalized MET; LC3C deletion abrogates Met entry into the autophagy-dependent degradative pathway, enhancing Met signaling and cell invasion.\",\n      \"method\": \"Co-immunoprecipitation, genetic deletion (LC3C KO), cell invasion assays, immunofluorescence\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex formation by Co-IP, genetic loss-of-function with specific phenotypic readout, domain rescue experiments; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31851933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAP1LC3C physically interacts with CALCOCO1, and genetic deletion of CALCOCO1 disrupts reticulophagy (selective autophagy of the endoplasmic reticulum), placing CALCOCO1-LC3C interaction in MTOR-regulated selective autophagy.\",\n      \"method\": \"Co-immunoprecipitation (mass spectrometry proteomics + direct interaction), genetic KO, reticulophagy assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification plus direct interaction validated, genetic KO with defined autophagy phenotype; single lab\",\n      \"pmids\": [\"31971854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LC3C autophagy requires a noncanonical upstream regulatory complex including ULK3, UVRAG, RUBCN, PIK3C2A, and TSG101 (an ESCRT member), distinct from canonical autophagy regulators; postdivision midbody rings (PDMBs) are direct targets of LC3C-dependent selective degradation, and the LC3C C-terminal 20-amino acid peptide (cleaved during Gly126 lipidation) is necessary and sufficient for PDMB degradation.\",\n      \"method\": \"Genetic knockdown/knockout, autophagy flux assays, domain truncation/rescue experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations with defined mechanistic outputs, domain-sufficiency experiments; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"33988680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LC3C interacts with cardiolipin (CL)-containing membranes in vitro but its colocalization with mitochondria is not rotenone-dependent, and loss of LC3C does not decrease CCCP-induced mitophagy, indicating LC3C does not participate in cargo recognition during CL-mediated mitophagy (negative finding).\",\n      \"method\": \"In vitro lipid-binding assays with model membranes, fluorescence colocalization in SH-SY5Y cells, siRNA knockdown with CCCP/rotenone-induced mitophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus cell-based colocalization plus functional mitophagy assay; single lab with multiple orthogonal methods; findings are explicitly negative for LC3C in mitophagy\",\n      \"pmids\": [\"35414338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of LC3C leads to peripheral positioning of lysosomes and lysosomal exocytosis (LE) independently of LC3C's autophagic activity; this LE is accompanied by transcriptomic reprogramming with altered zinc-related gene expression, decreased intracellular zinc, altered polycomb repressor complex 2 activity, and increased tumor initiation properties in xenograft models.\",\n      \"method\": \"Isogenic cell lines with LC3C loss, immunocytochemistry, metabolomics, transcriptomics, xenograft tumor assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary cellular and molecular methods; single lab, defined mechanistic dissection of autophagic vs. non-autophagic LC3C function\",\n      \"pmids\": [\"37003503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TFG (TRK-fused gene) facilitates ULK1-MAP1LC3C interaction to modulate omegasome and autophagosome formation under starvation conditions.\",\n      \"method\": \"Co-immunoprecipitation, autophagosome/omegasome formation assays (referenced from primary study)\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single commentary describing findings from primary study; abstract provides limited methodological detail; single lab\",\n      \"pmids\": [\"34616872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAP1LC3C plays a role in odontogenic differentiation of human dental pulp cells (DPCs): MAP1LC3C expression is selectively upregulated during odontogenic differentiation and shRNA knockdown of MAP1LC3C causes strong downregulation of odontogenic markers (DMP1 and DSPP), while knockdown of MAP1LC3B has lesser effect.\",\n      \"method\": \"shRNA knockdown, RT-qPCR, marker protein detection during odontogenic differentiation\",\n      \"journal\": \"Tissue engineering and regenerative medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — selective knockdown with specific differentiation marker readout, comparative with LC3B isoform; single lab, multiple markers\",\n      \"pmids\": [\"33230801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Silencing MAP1LC3C in tumor cells inhibits CIITA expression and suppresses HLA class II production, linking LC3C to antigen presentation machinery regulation.\",\n      \"method\": \"siRNA/shRNA silencing of MAP1LC3C, Western blot/RT-qPCR for CIITA and HLA class II\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, no reconstitution or direct interaction experiments described\",\n      \"pmids\": [\"39928678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Non-phosphorylated (Thr308-dephosphorylated) AKT1 acts as a scaffold to recruit SQSTM1, enabling PDPK1-dependent phosphorylation of SQSTM1 at Ser349 and selective loading of viral capsids into LC3C-positive phagophores for antiviral degradation.\",\n      \"method\": \"Genetic KO, phospho-mutant expression, co-immunoprecipitation, in vivo viral replication assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations (KO, phospho-mutant), biochemical interaction assays, in vivo validation; single lab\",\n      \"pmids\": [\"42152503\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAP1LC3C (LC3C) is a human-specific ATG8 family member that undergoes ATG4B-mediated C-terminal cleavage (requiring an Arg68–Asp171 salt bridge) followed by PE conjugation for autophagosome membrane association; it possesses a unique N-terminal polyproline II 'sticky arm' that can be phosphorylated at Ser18 by PKA to modulate LIR-binding surface conformation; it mediates selective autophagy through a noncanonical regulatory complex (ULK3/UVRAG/RUBCN/PIK3C2A/TSG101) using its C-terminal peptide to target postdivision midbody rings, interacts with CALCOCO1 for reticulophagy and with MET RTK for receptor degradation, and independently of autophagy controls lysosomal positioning and exocytosis to regulate intracellular zinc levels and tumor-suppressive functions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAP1LC3C (LC3C) is an ATG8-family ubiquitin-like protein that drives selective autophagy and, independently, governs lysosomal positioning to exert tumor-suppressive functions [#3, #7]. Like other ATG8 proteins, it is processed at its conserved C-terminal Gly residue and recruited to autophagosome membranes [#0]; this cleavage depends on a salt bridge between LC3C Arg68 and Asp171 of the cysteine protease ATG4B, which is required for downstream lipidation and autophagosome formation [#1]. LC3C is structurally distinguished by a unique N-terminal polyproline II 'sticky arm' on a flexible linker in place of the stable α1 helix of other LC3/GABARAP proteins, and phosphorylation of Ser18 at the linker-core interface by PKA remodels its LIR-binding surface [#2]. Through this surface and adaptor interactions, LC3C executes cargo-selective degradation: it complexes with the MET/HGF receptor tyrosine kinase to route activated, internalized MET into autophagic degradation and restrain MET signaling and cell invasion [#3], binds CALCOCO1 to mediate reticulophagy [#4], and uses a noncanonical upstream complex (ULK3, UVRAG, RUBCN, PIK3C2A, TSG101) together with its cleaved C-terminal 20-residue peptide to target postdivision midbody rings [#5]. Independently of its autophagic activity, loss of LC3C drives peripheral lysosome positioning and lysosomal exocytosis, lowering intracellular zinc, reprogramming the transcriptome, and increasing tumor-initiating capacity [#7]. LC3C does not participate in cardiolipin-mediated mitophagy [#6].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that LC3C, despite divergence from LC3B, behaves as a membrane-conjugating ATG8 protein answered whether this isoform is competent for the canonical autophagy lipidation cycle.\",\n      \"evidence\": \"Cell fractionation and immunofluorescence showing C-terminal cleavage after the conserved Gly and autophagosome membrane association\",\n      \"pmids\": [\"12740394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The protease responsible for cleavage was not identified\", \"Functional consequences and selectivity of LC3C autophagy were not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining the LC3C Arg68\\u2013ATG4B Asp171 salt bridge explained the molecular requirement for C-terminal processing and connected LC3C to the ATG4B cleavage machinery.\",\n      \"evidence\": \"Structural simulation, mutagenesis, and autophagic flux assays across ATG8 family members\",\n      \"pmids\": [\"23721406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Done by modeling plus mutagenesis without a co-crystal structure of LC3C-ATG4B\", \"Did not establish isoform-specific differences in processing kinetics\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Solving the unique N-terminal 'sticky arm' architecture and identifying Ser18 PKA phosphorylation revealed how LC3C's adaptor-binding surface can be conformationally regulated, distinguishing it from other LC3/GABARAP proteins.\",\n      \"evidence\": \"NMR spectroscopy, molecular dynamics simulations, and in vitro PKA kinase assay\",\n      \"pmids\": [\"31578424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ser18 phosphorylation shown in vitro; cellular kinase activity and physiological trigger not established\", \"Functional effect on specific cargo selection not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating LC3C-MET complex formation and LC3C-dependent MET degradation answered how a specific receptor tyrosine kinase is cleared by autophagy and linked LC3C to suppression of invasion.\",\n      \"evidence\": \"Co-immunoprecipitation, LC3C knockout, domain rescue, and cell invasion assays\",\n      \"pmids\": [\"31851933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. adaptor-bridged LC3C-MET binding not resolved\", \"Single lab; in vivo relevance of MET clearance not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying the LC3C-CALCOCO1 interaction placed LC3C in MTOR-regulated reticulophagy, expanding its selective-autophagy cargo repertoire to the ER.\",\n      \"evidence\": \"Proteomic and direct interaction validation with CALCOCO1 KO and reticulophagy assays\",\n      \"pmids\": [\"31971854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LC3C-specific contribution versus other ATG8 isoforms in reticulophagy not isolated\", \"Structural basis of the LC3C-CALCOCO1 LIR interaction not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking LC3C expression to odontogenic differentiation suggested a tissue-specific developmental role beyond bulk autophagy, with isoform selectivity over LC3B.\",\n      \"evidence\": \"shRNA knockdown and RT-qPCR/protein readout of DMP1 and DSPP markers in human dental pulp cells\",\n      \"pmids\": [\"33230801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting LC3C to odontogenic gene expression unknown\", \"Whether the effect depends on autophagy not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining a noncanonical upstream regulatory complex and the cleaved C-terminal peptide as the targeting determinant for postdivision midbody rings established that LC3C-driven selective autophagy uses dedicated machinery distinct from canonical autophagy.\",\n      \"evidence\": \"Genetic knockdown/knockout, autophagic flux assays, and domain truncation/sufficiency experiments\",\n      \"pmids\": [\"33988680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the ULK3/UVRAG/RUBCN/PIK3C2A/TSG101 components are assembled and ordered not resolved\", \"Direct binding partner of the C-terminal 20-aa peptide on PDMBs not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reporting that TFG facilitates ULK1-LC3C interaction proposed a bridging factor for omegasome/autophagosome formation under starvation.\",\n      \"evidence\": \"Co-immunoprecipitation and autophagosome/omegasome formation assays described in a commentary\",\n      \"pmids\": [\"34616872\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Low-confidence commentary with limited methodological detail; not independently confirmed\", \"Direct vs. indirect TFG-LC3C-ULK1 connectivity unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Testing LC3C in cardiolipin-mediated mitophagy answered whether its lipid-binding extends to mitochondrial cargo recognition, with a clear negative result.\",\n      \"evidence\": \"In vitro cardiolipin membrane binding, colocalization in SH-SY5Y cells, and siRNA with CCCP/rotenone mitophagy assays\",\n      \"pmids\": [\"35414338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not exclude LC3C roles in other forms of mitophagy\", \"In vitro CL binding without an identified physiological function\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Separating LC3C's autophagy-dependent and -independent functions revealed an autophagy-independent control of lysosomal positioning and exocytosis that regulates zinc and tumor initiation.\",\n      \"evidence\": \"Isogenic LC3C-loss cell lines, immunocytochemistry, metabolomics, transcriptomics, and xenograft tumor assays\",\n      \"pmids\": [\"37003503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which LC3C controls lysosome positioning not defined\", \"Causal chain from zinc changes to PRC2 activity and tumor initiation incompletely mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connecting LC3C silencing to reduced CIITA and HLA class II proposed a role in antigen-presentation machinery regulation in tumor cells.\",\n      \"evidence\": \"siRNA/shRNA silencing with CIITA and HLA class II readout by Western blot/RT-qPCR\",\n      \"pmids\": [\"39928678\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Low-confidence; no direct interaction or reconstitution experiments\", \"Mechanism linking LC3C to CIITA transcription unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defining an AKT1-scaffold/PDPK1/SQSTM1 axis that loads viral capsids into LC3C-positive phagophores established LC3C participation in antiviral selective autophagy.\",\n      \"evidence\": \"Genetic KO, phospho-mutant expression, co-immunoprecipitation, and in vivo viral replication assays\",\n      \"pmids\": [\"42152503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LC3C-SQSTM1 engagement during capsid loading not fully resolved\", \"Generalizability across virus families not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LC3C selects among its diverse cargoes (MET, ER, midbody rings, viral capsids) and how its Ser18 phosphorylation and unique 'sticky arm' tune adaptor choice in cells remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking sticky-arm conformation to cargo selectivity\", \"Physiological kinases/phosphatases governing Ser18 in vivo unidentified\", \"Molecular basis of the autophagy-independent lysosomal positioning function unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATG4B\", \"MET\", \"CALCOCO1\", \"ULK3\", \"UVRAG\", \"RUBCN\", \"PIK3C2A\", \"TSG101\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}