{"gene":"MAP1S","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2003,"finding":"MAP1S (VCY2IP-1) was identified as a direct binding partner of VCY2 using yeast two-hybrid, showing homology to MAP1A/MAP1B and mapping to chromosome 19p13.11. The interaction suggests MAP1S links VCY2 to the cytoskeletal network.","method":"Yeast two-hybrid, Northern blot, in situ hybridization","journal":"Biology of reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid, no functional validation of the interaction in mammalian cells","pmids":["14627543"],"is_preprint":false},{"year":2005,"finding":"C19ORF5/MAP1S (also called MAP1S) specifically accumulates on paclitaxel-stabilized microtubules and interacts directly with paclitaxel-stabilized microtubules in vitro. A C-terminal 393-residue domain (C19ORF5C) mediates microtubule binding through a highly basic region of <100 residues. Accumulation of MAP1S on stabilized microtubules progressively induces perinuclear mitochondrial aggregation and genome destruction (MAGD), mediated by a distinct 25-residue sequence (F967-A991) separate from the microtubule-binding domain. Deletion mutagenesis defined these two functional domains.","method":"Recombinant protein overexpression in mammalian cells, in vitro microtubule binding assay, deletion mutagenesis, immunofluorescence","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified microtubules, deletion mutagenesis identifying distinct domains, multiple orthogonal methods in one study","pmids":["15899810"],"is_preprint":false},{"year":2005,"finding":"C19ORF5/MAP1S interacts with RASSF1A and RASSF1C, and coexpression reveals that the unique N-terminal sequence of RASSF1C prevents it from hyperstabilizing microtubules, conferring specificity on RASSF1A for microtubule hyperstabilization and MAP1S accumulation on microtubules. Both RASSF1 isoforms share identical microtubule-association sequence domains.","method":"Coexpression in mammalian cells, colocalization, functional microtubule assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional coexpression with isoform specificity, multiple orthogonal observations, single lab","pmids":["15753381"],"is_preprint":false},{"year":2005,"finding":"The C-terminus of MAP1S (C19ORF5C) interacts with the mitochondria-associated DNA-binding protein LRPPRC in liver cells. MAP1S itself binds double-stranded DNA through its microtubule-binding domain, with affinity sufficient for DNA affinity chromatography, but exhibits no intrinsic DNase activity.","method":"Co-immunoprecipitation, DNA affinity chromatography, deletion mutagenesis, in vitro DNA binding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro DNA-binding assay, Co-IP with LRPPRC, deletion mutagenesis, single lab","pmids":["15907802"],"is_preprint":false},{"year":2007,"finding":"siRNA-mediated knockdown of MAP1S (C19ORF5) causes mitotic abnormalities including failure to form a stable metaphase plate, premature sister chromatid separation, lagging chromosomes, and multipolar spindles. MAP1S localizes to spindle microtubules and to microtubule-organizing centers during regrowth after nocodazole washout. Knockdown disrupts the MTOC and alters alpha- and gamma-tubulin localization and sites of nucleation. The N-terminus of MAP1S is essential for MTOC anchoring.","method":"siRNA knockdown, time-lapse video microscopy, immunofluorescence, nocodazole washout assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean siRNA KD with defined mitotic phenotypes, live imaging, multiple orthogonal readouts, supported by prior structural work on the same protein","pmids":["17234756"],"is_preprint":false},{"year":2010,"finding":"MAP1S binds prestin (SLC26A5) via the prestin STAS domain and the region connecting the heavy and light chain of MAP1S, identified by yeast two-hybrid and confirmed by reciprocal immunoprecipitation and FRET. Co-expression of prestin with MAP1S results in a 2.7-fold increase in voltage-evoked charge density and a 2.8-fold increase in prestin surface expression in transfected cells.","method":"Yeast two-hybrid, reciprocal co-immunoprecipitation, FRET, electrophysiology, surface expression quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, FRET, and functional electrophysiological readout in one study, multiple orthogonal methods","pmids":["20418376"],"is_preprint":false},{"year":2011,"finding":"MAP1S isoforms interact with the autophagosome-associated protein LC3 and recruit it to stable microtubules in an isoform-dependent manner. MAP1S also interacts with the mitochondria-associated protein LRPPRC, which interacts with the mitophagy initiator Parkin. MAP1S knockout mice exhibit reduced Bcl-2/xL and P27 protein levels, accumulation of defective mitochondria, and severe defects in response to nutritive stress, indicating roles in autophagosomal biogenesis and clearance.","method":"Co-immunoprecipitation, MAP1S knockout mice, immunofluorescence, cellular stress assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO mouse model with defined phenotypes, multiple orthogonal approaches, replicated interaction with LRPPRC from prior work","pmids":["21262964"],"is_preprint":false},{"year":2011,"finding":"Elevation of MAP1S levels in mouse liver in response to diethylnitrosamine-induced or genome instability-driven metabolic stress enhances autophagy to remove p62-associated aggresomes and dysfunctional organelles, thereby reducing DNA double-strand breaks, genome instability, and suppressing hepatocarcinogenesis.","method":"MAP1S KO and overexpression mouse models, diethylnitrosamine-induced hepatocarcinoma model, genome stability assays, autophagy flux measurements","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO/overexpression in in vivo mouse cancer model with mechanistic pathway dissection, multiple readouts","pmids":["22037873"],"is_preprint":false},{"year":2012,"finding":"MAP1S (MAP8) interacts with nemitin, a novel LisH/WD40 repeat protein enriched in the nervous system. Co-expression of nemitin with MAP1S results in nemitin redistributing from a diffuse cytosolic pattern to decorating microtubules uniformly, indicating MAP1S mediates nemitin's association with microtubules.","method":"Co-expression in non-neuronal cells, immunofluorescence, co-IP","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-expression redistribution assay and protein interaction, single lab, two orthogonal methods","pmids":["22523538"],"is_preprint":false},{"year":2014,"finding":"MAP1S knockdown alters microtubule dynamics throughout the cell cycle, resulting in faster-growing but short-lived microtubules and a global loss of microtubule acetylation. MAP1S guides MT-dependent initiation of cytokinesis as shown in monopolar cytokinesis assays.","method":"siRNA knockdown, quantitative MT plus-end tracking, monopolar cytokinesis assay, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — quantitative live-cell MT dynamics tracking after KD, monopolar cytokinesis assay, multiple orthogonal methods in one study","pmids":["25300793"],"is_preprint":false},{"year":2014,"finding":"PU.1 transcription factor binds the MAP1S promoter and induces MAP1S expression during neutrophil/APL differentiation. Inhibiting MAP1S in this context results in aberrant neutrophil differentiation and impaired autophagy.","method":"ChIP assay (PU.1 binding to MAP1S promoter), siRNA knockdown, differentiation assays, autophagy assays","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates direct promoter binding, KD with defined differentiation and autophagy phenotype, single lab","pmids":["25043887"],"is_preprint":false},{"year":2014,"finding":"MAP1S regulates TLR5/flagellin signaling in breast cancer cells by enhancing NF-κB activity and cytokine secretion. MAP1S knockdown abolishes flagellin-mediated tumor growth suppression and migration inhibition. MAP1S also mediates degradation of MyD88 via autophagy upon TLR activation.","method":"siRNA knockdown, tumor growth assays, cytokine measurements, NF-κB reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined signaling and tumor phenotype, single lab, pathway placement via KD epistasis","pmids":["24466264"],"is_preprint":false},{"year":2015,"finding":"MAP1S interacts with HDAC4 via a defined HDAC4-binding domain (HBD) on MAP1S. HDAC4 destabilizes MAP1S by increasing its deacetylation, suppresses autophagy flux, and promotes accumulation of mutant huntingtin aggregates. Suppression of HDAC4 or overexpression of the MAP1S HBD stabilizes MAP1S, activates autophagy flux, and clears mHTT aggregates.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression of HBD domain, autophagy flux assays, aggregate quantification","journal":"Aging","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying binding domain, functional rescue and epistasis experiments, multiple orthogonal methods in one study","pmids":["26540094"],"is_preprint":false},{"year":2015,"finding":"MAP1S interacts directly with MyD88 upon TLR activation and affects the TLR signaling pathway. MAP1S-deficient macrophages are impaired in bacterial phagocytosis. Upon TLR activation, MyD88 participates in autophagy processing in a MAP1S-dependent manner by co-localizing with LC3.","method":"Co-immunoprecipitation, MAP1S KO macrophages, phagocytosis assays, co-localization with LC3","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP with MyD88, KO cells with phagocytosis phenotype, co-localization, single lab","pmids":["26565030"],"is_preprint":false},{"year":2016,"finding":"MAP1S promotes autophagic clearance of lipid droplets (coated by ADFP) in renal cells. Suppression of MAP1S impairs autophagic clearance, while overexpression activates autophagy flux and reduces lipid droplets and associated DNA double-strand breaks.","method":"MAP1S KD/overexpression, autophagy flux assays, lipid droplet quantification, DNA damage assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined autophagic substrate phenotype, single lab","pmids":["26701856"],"is_preprint":false},{"year":2016,"finding":"MAP1S-mediated autophagy is required for lysosomal degradation of fibronectin. In MAP1S-deficient mice, LC3-driven synthesis of fibronectin accumulates because MAP1S depletion impairs lysosomal degradation, causing liver fibrosis, oxidative stress, and lifespan reduction.","method":"MAP1S KO mice, LC3 transgenic mice, Western blot, autophagy flux assays, fibronectin quantification, lifespan analysis","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO and transgenic mouse models with defined biochemical substrate (fibronectin) and phenotypic outcomes, replicated in renal fibrosis study","pmids":["26750654","27236336"],"is_preprint":false},{"year":2017,"finding":"MAP1S interacts with LC3 and positively regulates autophagy flux. MAP1S stability is regulated by HDAC4, which destabilizes it. Spermidine depletes cytosolic HDAC4, thereby stabilizing MAP1S and enhancing autophagy. MAP1S-deficient mice show reduced lifespan and develop liver fibrosis and HCC; spermidine's lifespan extension and liver protection are dependent on MAP1S-mediated autophagy.","method":"Co-immunoprecipitation, MAP1S KO mice, spermidine treatment, genetic epistasis (MAP1S KO abolishes spermidine effects), autophagy flux assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via KO mice, Co-IP, multiple in vivo and in vitro approaches, replicated HDAC4-MAP1S interaction from prior study","pmids":["28386016"],"is_preprint":false},{"year":2019,"finding":"MAP1S activates NRF2 signaling through two parallel mechanisms: (1) MAP1S competes with KEAP1 for NRF2 binding via an ETGE motif present on MAP1S, stabilizing NRF2; (2) MAP1S accelerates p62-dependent autophagic degradation of KEAP1. Both mechanisms result in NRF2 stabilization. Spermidine-mediated liver protection requires both NRF2 and p62-dependent autophagy pathways.","method":"Co-immunoprecipitation, competitive binding assays, autophagy assays, Nrf2 KO / p62 KO / double KO mouse models with CCl4-induced liver fibrosis","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating ETGE-motif-mediated competition, multiple KO mouse models for epistasis, two distinct parallel mechanisms characterized","pmids":["30873635"],"is_preprint":false},{"year":2021,"finding":"RASSF1A interacts with MAP1S (confirmed by Co-IP) and regulates MAP1S to inactivate the Keap1-Nrf2 pathway, thereby activating autophagy and enhancing chemosensitivity to cisplatin in NSCLC cells.","method":"Co-immunoprecipitation, overexpression/knockdown, autophagy assays (LC3 puncta, Western blot), xenograft model","journal":"Drug design, development and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, functional rescue in cells and in vivo, but single lab and pathway placement relies partly on prior studies","pmids":["33442234"],"is_preprint":false},{"year":2024,"finding":"MAP1S promotes degradation of HDAC6 via autophagy, leading to increased microtubule acetylation and nuclear translocation of the Smad complex, thereby enhancing downstream TGF-β signaling. HBV X protein upregulates MAP1S to establish a MAP1S/Smad/TGF-β1 feedback loop promoting HCC proliferation and migration.","method":"MAP1S knockdown in vitro and in vivo, Western blot, nuclear fractionation, Co-IP, tumor growth assays","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined mechanistic pathway (HDAC6 degradation → MT acetylation → Smad nuclear translocation), single lab","pmids":["39374711"],"is_preprint":false},{"year":2025,"finding":"CDKL5 phosphorylates MAP1S at S786 and S812, regulating MAP1S binding to microtubules. MAP1S phosphomutant (S786/812A) mice show severely reduced dynein binding to microtubules, impaired dynein motility in neurons, reduced delivery of AMPA receptors in dendrites, reduced tubulin tyrosination, decreased spine density and synapses, and behavioral deficits. Expression of tubulin tyrosine kinase TTL rescues dynein motility defects, placing MAP1S phosphorylation upstream of tubulin tyrosination and dynein-mediated transport.","method":"MAP1S phosphomutant knock-in mice, microtubule co-sedimentation assay, time-lapse live imaging in neurons, dendritic cargo tracking, TTL rescue experiment, behavioral phenotyping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphomutant KI mice, co-sedimentation, live imaging, genetic rescue, multiple orthogonal methods, but preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.08.28.610038"],"is_preprint":true},{"year":2025,"finding":"SRPK directly phosphorylates MAP1S at multiple sites in a C-terminal region involved in proteolytic maturation and microtubule binding. SRPK-dependent MAP1S phosphorylation modulates the affinity of the MAP1S microtubule-binding domain for microtubules and MAP1S proteolytic processing by the Calpain-10 (CAPN10) protease. MAP1S proteolytic processing occurs progressively during neurodevelopment via a specific CAPN10 expression switch, corresponding with MAP1S acquisition of microtubule binding activity.","method":"Global phosphoproteomic screening, in vitro kinase assay, microtubule binding assays, proteolytic processing assays, developmental expression analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay and functional binding/processing assays, but preprint not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.09.19.677315"],"is_preprint":true},{"year":2025,"finding":"Alpha-tubulin is arginylated at E77 by ATE1, and loss of this arginylation (Ate1-/- cells or tubulinE77A overexpression) increases the fraction of MAP1S associated with microtubules. MAP1S knockdown rescues the reduced microtubule growth rate and increased stability seen in Ate1-/- cells to wild-type levels, demonstrating that E77 arginylation directly regulates MAP1S microtubule binding and thereby controls microtubule dynamics.","method":"Ate1 KO cells, alpha-tubulinE77A overexpression, Map1s siRNA knockdown, microtubule co-sedimentation, live-cell MT dynamics imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic models (KO, phosphomutant), functional rescue by Map1s KD, co-sedimentation, mechanistic epistasis established","pmids":["39852692"],"is_preprint":false}],"current_model":"MAP1S is a microtubule-associated protein that bridges the autophagy machinery (via direct LC3 interaction), microtubules, and mitochondria (via LRPPRC interaction) to positively regulate autophagy flux from autophagosomal biogenesis through lysosomal degradation; its stability is controlled by HDAC4-mediated deacetylation, its microtubule binding is regulated by CDKL5 phosphorylation (S786/S812) and alpha-tubulin arginylation at E77, it activates NRF2 by competing with KEAP1 for NRF2 binding (via an ETGE motif) and by promoting p62-dependent autophagic KEAP1 degradation, it interacts with RASSF1A to regulate mitotic fidelity and tumor suppression, and it modulates TLR/MyD88 and TGF-β/Smad signaling pathways, with loss-of-function in mice causing mitotic defects, accumulation of dysfunctional organelles and fibronectin, liver fibrosis, renal fibrosis, genomic instability, and reduced lifespan."},"narrative":{"mechanistic_narrative":"MAP1S is a microtubule-associated protein that couples the microtubule cytoskeleton to autophagy, mitochondrial quality control, and mitotic fidelity [PMID:15899810, PMID:21262964, PMID:17234756]. It binds and accumulates on stabilized microtubules through a basic C-terminal microtubule-binding domain, while a distinct C-terminal sequence drives perinuclear mitochondrial aggregation and genome destruction upon overexpression [PMID:15899810]; its N-terminus is required for anchoring to microtubule-organizing centers, and loss of MAP1S disrupts spindle architecture, tubulin nucleation, microtubule dynamics, and cytokinesis, producing premature sister-chromatid separation, lagging chromosomes, and multipolar spindles [PMID:17234756, PMID:25300793]. In autophagy, MAP1S directly binds LC3 and recruits it to stable microtubules, and through its interaction with the mitochondria-associated protein LRPPRC it links autophagosomal biogenesis to clearance of defective mitochondria and other dysfunctional organelles [PMID:21262964]. MAP1S thereby drives autophagic degradation of diverse substrates—p62-associated aggresomes, lipid droplets, fibronectin, mutant huntingtin aggregates, and MyD88—and its loss in mice causes accumulation of these cargoes, genome instability, liver and renal fibrosis, oxidative stress, and reduced lifespan [PMID:22037873, PMID:26701856, PMID:26750654, PMID:27236336, PMID:26540094, PMID:26565030]. MAP1S protein stability is controlled by HDAC4, which destabilizes it via deacetylation; the polyamine spermidine depletes cytosolic HDAC4 to stabilize MAP1S and enhance autophagy, an effect genetically dependent on MAP1S [PMID:26540094, PMID:28386016]. MAP1S also activates NRF2 by competing with KEAP1 for NRF2 binding through an ETGE motif and by accelerating p62-dependent autophagic degradation of KEAP1 [PMID:30873635]. Its microtubule binding is further tuned by post-translational inputs, including CDKL5 phosphorylation at S786/S812 that governs dynein-mediated transport and tubulin tyrosination in neurons, and alpha-tubulin arginylation at E77 by ATE1 [PMID:bio_10.1101_2024.08.28.610038, PMID:39852692]. MAP1S interacts with RASSF1A to influence microtubule hyperstabilization and chemosensitivity [PMID:15753381, PMID:33442234].","teleology":[{"year":2003,"claim":"Established the existence of MAP1S as a MAP1A/MAP1B-homologous protein and a candidate cytoskeletal adaptor, answering what gene/protein this locus encodes.","evidence":"Yeast two-hybrid against VCY2, Northern blot, in situ hybridization","pmids":["14627543"],"confidence":"Low","gaps":["VCY2 interaction never functionally validated in mammalian cells","no demonstrated cytoskeletal function at this stage"]},{"year":2005,"claim":"Defined MAP1S as a genuine microtubule-binding protein with separable functional domains, resolving how it engages microtubules versus triggering organelle/genome destruction.","evidence":"In vitro microtubule binding with purified tubulin, deletion mutagenesis, immunofluorescence in mammalian cells","pmids":["15899810"],"confidence":"High","gaps":["physiological trigger of MAGD phenotype unclear","domain boundaries not validated structurally"]},{"year":2005,"claim":"Connected MAP1S to RASSF1A-dependent microtubule hyperstabilization and to mitochondria/DNA through LRPPRC binding and intrinsic dsDNA binding, framing MAP1S as a hub linking cytoskeleton to mitochondria and genome.","evidence":"Coexpression colocalization assays; Co-IP with LRPPRC, DNA affinity chromatography, in vitro DNA binding","pmids":["15753381","15907802"],"confidence":"Medium","gaps":["functional consequence of DNA binding not established (no DNase activity)","single-lab interaction data without reciprocal structural mapping"]},{"year":2007,"claim":"Demonstrated a required mitotic role for MAP1S, answering whether the protein is functionally needed at the spindle and MTOC rather than merely binding microtubules when overexpressed.","evidence":"siRNA knockdown, time-lapse microscopy, nocodazole washout, immunofluorescence","pmids":["17234756"],"confidence":"High","gaps":["molecular mechanism of MTOC anchoring by the N-terminus undefined","link to tubulin nucleation machinery not resolved"]},{"year":2011,"claim":"Identified MAP1S as a positive regulator of autophagy via direct LC3 binding and LRPPRC/Parkin-linked mitophagy, establishing the autophagy axis that became its central characterized function.","evidence":"Co-IP, MAP1S knockout mice, immunofluorescence, nutritive-stress assays; in vivo DEN hepatocarcinoma model","pmids":["21262964","22037873"],"confidence":"High","gaps":["how LC3 recruitment to microtubules couples to autophagosome maturation not mechanistically detailed","relationship between mitotic and autophagic roles unresolved"]},{"year":2014,"claim":"Extended MAP1S beyond mitosis and cancer into microtubule dynamics control, transcriptional induction during differentiation, and innate-immune/TLR signaling, broadening its functional scope.","evidence":"MT plus-end tracking and monopolar cytokinesis assays; PU.1 ChIP at the MAP1S promoter; TLR5/flagellin signaling and MyD88 autophagy assays with knockdown","pmids":["25300793","25043887","24466264"],"confidence":"Medium","gaps":["mechanism linking MAP1S to global MT acetylation not defined","TLR/MyD88 pathway placement relies on knockdown epistasis in single labs"]},{"year":2015,"claim":"Identified HDAC4 as a regulator of MAP1S stability and MyD88 as a direct autophagic substrate, answering how MAP1S levels are controlled and how it executes selective cargo clearance.","evidence":"Co-IP defining HDAC4-binding domain, HBD overexpression rescue, autophagy flux and aggregate assays; Co-IP with MyD88, MAP1S KO macrophage phagocytosis and LC3 colocalization","pmids":["26540094","26565030"],"confidence":"High","gaps":["how deacetylation destabilizes MAP1S mechanistically unclear","MyD88 interaction characterized in single lab"]},{"year":2016,"claim":"Established specific autophagic substrates (lipid droplets, fibronectin) whose accumulation drives organ fibrosis and shortened lifespan, linking MAP1S autophagy directly to disease-relevant pathology.","evidence":"MAP1S KD/overexpression and KO/LC3-transgenic mice, autophagy flux, substrate quantification, lifespan analysis","pmids":["26701856","26750654","27236336"],"confidence":"High","gaps":["selectivity mechanism distinguishing these cargoes from others not defined","lysosomal degradation step mechanistically uncharacterized"]},{"year":2017,"claim":"Placed MAP1S downstream of the polyamine spermidine via HDAC4-dependent stabilization, providing a pharmacological lever on MAP1S-mediated autophagy and lifespan.","evidence":"Co-IP, MAP1S KO mice, spermidine treatment with genetic epistasis, autophagy flux assays","pmids":["28386016"],"confidence":"High","gaps":["how spermidine depletes cytosolic HDAC4 not resolved","translational relevance beyond mouse liver unestablished"]},{"year":2019,"claim":"Resolved a dual mechanism by which MAP1S activates NRF2 — ETGE-mediated competition with KEAP1 and p62-dependent autophagic KEAP1 degradation — connecting MAP1S to antioxidant defense.","evidence":"Co-IP, competitive binding assays, autophagy assays, Nrf2/p62/double KO mice in CCl4 fibrosis model","pmids":["30873635"],"confidence":"High","gaps":["relative contribution of the two parallel mechanisms not quantified","ETGE-KEAP1 interface not structurally mapped"]},{"year":2021,"claim":"Linked RASSF1A regulation of MAP1S to KEAP1-NRF2 inactivation and cisplatin chemosensitivity, tying the early RASSF1A interaction into the autophagy/NRF2 framework.","evidence":"Co-IP, overexpression/knockdown, autophagy assays, xenograft model","pmids":["33442234"],"confidence":"Medium","gaps":["mechanism of RASSF1A regulation of MAP1S not defined","pathway placement partly inferred from prior studies"]},{"year":2024,"claim":"Identified a MAP1S/HDAC6/Smad axis whereby MAP1S-driven autophagic HDAC6 degradation increases MT acetylation and Smad nuclear translocation, implicating MAP1S in TGF-β signaling and HBV-driven HCC.","evidence":"MAP1S knockdown in vitro and in vivo, nuclear fractionation, Co-IP, tumor growth assays","pmids":["39374711"],"confidence":"Medium","gaps":["HDAC6 as a direct autophagy substrate not biochemically confirmed","single-lab pathway epistasis"]},{"year":2025,"claim":"Defined post-translational control of MAP1S microtubule binding by CDKL5 phosphorylation, SRPK phosphorylation/CAPN10 proteolytic maturation, and alpha-tubulin E77 arginylation, explaining how MAP1S microtubule affinity and dynein-dependent transport are regulated developmentally.","evidence":"Phosphomutant knock-in mice with live imaging and TTL rescue (preprint); phosphoproteomics, in vitro kinase and processing assays (preprint); Ate1 KO cells, tubulinE77A, Map1s siRNA rescue, co-sedimentation","pmids":["bio_10.1101_2024.08.28.610038","bio_10.1101_2025.09.19.677315","39852692"],"confidence":"Medium","gaps":["two of three studies are unreviewed preprints","integration of phosphorylation, proteolysis, and arginylation inputs not unified","structural basis of regulated MT binding unknown"]},{"year":null,"claim":"How MAP1S coordinates its distinct roles—mitotic spindle/MTOC function, selective autophagic cargo recognition, and NRF2/TGF-β signaling—into a single regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no high-resolution structure of MAP1S or its domain complexes","selectivity determinants for autophagic substrates undefined","no direct evidence linking the genome-instability/mitotic role to the autophagy role mechanistically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,4,9,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,8,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,17]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,9,22]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,7,15,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,13]}],"complexes":[],"partners":["LC3","LRPPRC","RASSF1A","HDAC4","MYD88","KEAP1","NRF2","CDKL5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q66K74","full_name":"Microtubule-associated protein 1S","aliases":["BPY2-interacting protein 1","Microtubule-associated protein 8","Variable charge Y chromosome 2-interacting protein 1","VCY2-interacting protein 1","VCY2IP-1"],"length_aa":1059,"mass_kda":112.2,"function":"Microtubule-associated protein that mediates aggregation of mitochondria resulting in cell death and genomic destruction (MAGD). Plays a role in anchoring the microtubule organizing center to the centrosomes. Binds to DNA. Plays a role in apoptosis. Involved in the formation of microtubule bundles (By similarity)","subcellular_location":"Nucleus; Cytoplasm, cytosol; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q66K74/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP1S","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":[{"gene":"STK4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAP1S","total_profiled":1310},"omim":[{"mim_id":"615734","title":"WD REPEAT-CONTAINING PROTEIN 47; WDR47","url":"https://www.omim.org/entry/615734"},{"mim_id":"607573","title":"MICROTUBULE-ASSOCIATED PROTEIN 1S; MAP1S","url":"https://www.omim.org/entry/607573"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Principal piece","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAP1S"},"hgnc":{"alias_symbol":["FLJ10669","MAP8"],"prev_symbol":["C19orf5","VCY2IP1","BPY2IP1"]},"alphafold":{"accession":"Q66K74","domains":[{"cath_id":"-","chopping":"15-218","consensus_level":"high","plddt":88.0806,"start":15,"end":218},{"cath_id":"3.60.15,3.60.15","chopping":"243-463_945-1059","consensus_level":"medium","plddt":89.7252,"start":243,"end":1059}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q66K74","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q66K74-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q66K74-F1-predicted_aligned_error_v6.png","plddt_mean":65.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP1S","jax_strain_url":"https://www.jax.org/strain/search?query=MAP1S"},"sequence":{"accession":"Q66K74","fasta_url":"https://rest.uniprot.org/uniprotkb/Q66K74.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q66K74/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q66K74"}},"corpus_meta":[{"pmid":"28386016","id":"PMC_28386016","title":"Spermidine 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biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39374711","citation_count":4,"is_preprint":false},{"pmid":"39852692","id":"PMC_39852692","title":"Arginylation of ⍺-tubulin at E77 regulates microtubule dynamics via MAP1S.","date":"2025","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39852692","citation_count":3,"is_preprint":false},{"pmid":"41906106","id":"PMC_41906106","title":"A mechanistic study revealing that SLCO1B3 promotes gastric cancer development and metastasis through MAP1S expression downregulation.","date":"2026","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41906106","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.19.677315","title":"Phosphorylation enables progressive microtubule-associated protein proteolysis and functionalisation during neural 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using yeast two-hybrid, showing homology to MAP1A/MAP1B and mapping to chromosome 19p13.11. The interaction suggests MAP1S links VCY2 to the cytoskeletal network.\",\n      \"method\": \"Yeast two-hybrid, Northern blot, in situ hybridization\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid, no functional validation of the interaction in mammalian cells\",\n      \"pmids\": [\"14627543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"C19ORF5/MAP1S (also called MAP1S) specifically accumulates on paclitaxel-stabilized microtubules and interacts directly with paclitaxel-stabilized microtubules in vitro. A C-terminal 393-residue domain (C19ORF5C) mediates microtubule binding through a highly basic region of <100 residues. Accumulation of MAP1S on stabilized microtubules progressively induces perinuclear mitochondrial aggregation and genome destruction (MAGD), mediated by a distinct 25-residue sequence (F967-A991) separate from the microtubule-binding domain. Deletion mutagenesis defined these two functional domains.\",\n      \"method\": \"Recombinant protein overexpression in mammalian cells, in vitro microtubule binding assay, deletion mutagenesis, immunofluorescence\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified microtubules, deletion mutagenesis identifying distinct domains, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15899810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"C19ORF5/MAP1S interacts with RASSF1A and RASSF1C, and coexpression reveals that the unique N-terminal sequence of RASSF1C prevents it from hyperstabilizing microtubules, conferring specificity on RASSF1A for microtubule hyperstabilization and MAP1S accumulation on microtubules. Both RASSF1 isoforms share identical microtubule-association sequence domains.\",\n      \"method\": \"Coexpression in mammalian cells, colocalization, functional microtubule assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional coexpression with isoform specificity, multiple orthogonal observations, single lab\",\n      \"pmids\": [\"15753381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The C-terminus of MAP1S (C19ORF5C) interacts with the mitochondria-associated DNA-binding protein LRPPRC in liver cells. MAP1S itself binds double-stranded DNA through its microtubule-binding domain, with affinity sufficient for DNA affinity chromatography, but exhibits no intrinsic DNase activity.\",\n      \"method\": \"Co-immunoprecipitation, DNA affinity chromatography, deletion mutagenesis, in vitro DNA binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro DNA-binding assay, Co-IP with LRPPRC, deletion mutagenesis, single lab\",\n      \"pmids\": [\"15907802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"siRNA-mediated knockdown of MAP1S (C19ORF5) causes mitotic abnormalities including failure to form a stable metaphase plate, premature sister chromatid separation, lagging chromosomes, and multipolar spindles. MAP1S localizes to spindle microtubules and to microtubule-organizing centers during regrowth after nocodazole washout. Knockdown disrupts the MTOC and alters alpha- and gamma-tubulin localization and sites of nucleation. The N-terminus of MAP1S is essential for MTOC anchoring.\",\n      \"method\": \"siRNA knockdown, time-lapse video microscopy, immunofluorescence, nocodazole washout assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean siRNA KD with defined mitotic phenotypes, live imaging, multiple orthogonal readouts, supported by prior structural work on the same protein\",\n      \"pmids\": [\"17234756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAP1S binds prestin (SLC26A5) via the prestin STAS domain and the region connecting the heavy and light chain of MAP1S, identified by yeast two-hybrid and confirmed by reciprocal immunoprecipitation and FRET. Co-expression of prestin with MAP1S results in a 2.7-fold increase in voltage-evoked charge density and a 2.8-fold increase in prestin surface expression in transfected cells.\",\n      \"method\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, FRET, electrophysiology, surface expression quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, FRET, and functional electrophysiological readout in one study, multiple orthogonal methods\",\n      \"pmids\": [\"20418376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAP1S isoforms interact with the autophagosome-associated protein LC3 and recruit it to stable microtubules in an isoform-dependent manner. MAP1S also interacts with the mitochondria-associated protein LRPPRC, which interacts with the mitophagy initiator Parkin. MAP1S knockout mice exhibit reduced Bcl-2/xL and P27 protein levels, accumulation of defective mitochondria, and severe defects in response to nutritive stress, indicating roles in autophagosomal biogenesis and clearance.\",\n      \"method\": \"Co-immunoprecipitation, MAP1S knockout mice, immunofluorescence, cellular stress assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO mouse model with defined phenotypes, multiple orthogonal approaches, replicated interaction with LRPPRC from prior work\",\n      \"pmids\": [\"21262964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Elevation of MAP1S levels in mouse liver in response to diethylnitrosamine-induced or genome instability-driven metabolic stress enhances autophagy to remove p62-associated aggresomes and dysfunctional organelles, thereby reducing DNA double-strand breaks, genome instability, and suppressing hepatocarcinogenesis.\",\n      \"method\": \"MAP1S KO and overexpression mouse models, diethylnitrosamine-induced hepatocarcinoma model, genome stability assays, autophagy flux measurements\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO/overexpression in in vivo mouse cancer model with mechanistic pathway dissection, multiple readouts\",\n      \"pmids\": [\"22037873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAP1S (MAP8) interacts with nemitin, a novel LisH/WD40 repeat protein enriched in the nervous system. Co-expression of nemitin with MAP1S results in nemitin redistributing from a diffuse cytosolic pattern to decorating microtubules uniformly, indicating MAP1S mediates nemitin's association with microtubules.\",\n      \"method\": \"Co-expression in non-neuronal cells, immunofluorescence, co-IP\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-expression redistribution assay and protein interaction, single lab, two orthogonal methods\",\n      \"pmids\": [\"22523538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAP1S knockdown alters microtubule dynamics throughout the cell cycle, resulting in faster-growing but short-lived microtubules and a global loss of microtubule acetylation. MAP1S guides MT-dependent initiation of cytokinesis as shown in monopolar cytokinesis assays.\",\n      \"method\": \"siRNA knockdown, quantitative MT plus-end tracking, monopolar cytokinesis assay, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative live-cell MT dynamics tracking after KD, monopolar cytokinesis assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25300793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PU.1 transcription factor binds the MAP1S promoter and induces MAP1S expression during neutrophil/APL differentiation. Inhibiting MAP1S in this context results in aberrant neutrophil differentiation and impaired autophagy.\",\n      \"method\": \"ChIP assay (PU.1 binding to MAP1S promoter), siRNA knockdown, differentiation assays, autophagy assays\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates direct promoter binding, KD with defined differentiation and autophagy phenotype, single lab\",\n      \"pmids\": [\"25043887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAP1S regulates TLR5/flagellin signaling in breast cancer cells by enhancing NF-κB activity and cytokine secretion. MAP1S knockdown abolishes flagellin-mediated tumor growth suppression and migration inhibition. MAP1S also mediates degradation of MyD88 via autophagy upon TLR activation.\",\n      \"method\": \"siRNA knockdown, tumor growth assays, cytokine measurements, NF-κB reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined signaling and tumor phenotype, single lab, pathway placement via KD epistasis\",\n      \"pmids\": [\"24466264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAP1S interacts with HDAC4 via a defined HDAC4-binding domain (HBD) on MAP1S. HDAC4 destabilizes MAP1S by increasing its deacetylation, suppresses autophagy flux, and promotes accumulation of mutant huntingtin aggregates. Suppression of HDAC4 or overexpression of the MAP1S HBD stabilizes MAP1S, activates autophagy flux, and clears mHTT aggregates.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression of HBD domain, autophagy flux assays, aggregate quantification\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying binding domain, functional rescue and epistasis experiments, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26540094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAP1S interacts directly with MyD88 upon TLR activation and affects the TLR signaling pathway. MAP1S-deficient macrophages are impaired in bacterial phagocytosis. Upon TLR activation, MyD88 participates in autophagy processing in a MAP1S-dependent manner by co-localizing with LC3.\",\n      \"method\": \"Co-immunoprecipitation, MAP1S KO macrophages, phagocytosis assays, co-localization with LC3\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP with MyD88, KO cells with phagocytosis phenotype, co-localization, single lab\",\n      \"pmids\": [\"26565030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAP1S promotes autophagic clearance of lipid droplets (coated by ADFP) in renal cells. Suppression of MAP1S impairs autophagic clearance, while overexpression activates autophagy flux and reduces lipid droplets and associated DNA double-strand breaks.\",\n      \"method\": \"MAP1S KD/overexpression, autophagy flux assays, lipid droplet quantification, DNA damage assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined autophagic substrate phenotype, single lab\",\n      \"pmids\": [\"26701856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAP1S-mediated autophagy is required for lysosomal degradation of fibronectin. In MAP1S-deficient mice, LC3-driven synthesis of fibronectin accumulates because MAP1S depletion impairs lysosomal degradation, causing liver fibrosis, oxidative stress, and lifespan reduction.\",\n      \"method\": \"MAP1S KO mice, LC3 transgenic mice, Western blot, autophagy flux assays, fibronectin quantification, lifespan analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO and transgenic mouse models with defined biochemical substrate (fibronectin) and phenotypic outcomes, replicated in renal fibrosis study\",\n      \"pmids\": [\"26750654\", \"27236336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAP1S interacts with LC3 and positively regulates autophagy flux. MAP1S stability is regulated by HDAC4, which destabilizes it. Spermidine depletes cytosolic HDAC4, thereby stabilizing MAP1S and enhancing autophagy. MAP1S-deficient mice show reduced lifespan and develop liver fibrosis and HCC; spermidine's lifespan extension and liver protection are dependent on MAP1S-mediated autophagy.\",\n      \"method\": \"Co-immunoprecipitation, MAP1S KO mice, spermidine treatment, genetic epistasis (MAP1S KO abolishes spermidine effects), autophagy flux assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via KO mice, Co-IP, multiple in vivo and in vitro approaches, replicated HDAC4-MAP1S interaction from prior study\",\n      \"pmids\": [\"28386016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAP1S activates NRF2 signaling through two parallel mechanisms: (1) MAP1S competes with KEAP1 for NRF2 binding via an ETGE motif present on MAP1S, stabilizing NRF2; (2) MAP1S accelerates p62-dependent autophagic degradation of KEAP1. Both mechanisms result in NRF2 stabilization. Spermidine-mediated liver protection requires both NRF2 and p62-dependent autophagy pathways.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, autophagy assays, Nrf2 KO / p62 KO / double KO mouse models with CCl4-induced liver fibrosis\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating ETGE-motif-mediated competition, multiple KO mouse models for epistasis, two distinct parallel mechanisms characterized\",\n      \"pmids\": [\"30873635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RASSF1A interacts with MAP1S (confirmed by Co-IP) and regulates MAP1S to inactivate the Keap1-Nrf2 pathway, thereby activating autophagy and enhancing chemosensitivity to cisplatin in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, autophagy assays (LC3 puncta, Western blot), xenograft model\",\n      \"journal\": \"Drug design, development and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, functional rescue in cells and in vivo, but single lab and pathway placement relies partly on prior studies\",\n      \"pmids\": [\"33442234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAP1S promotes degradation of HDAC6 via autophagy, leading to increased microtubule acetylation and nuclear translocation of the Smad complex, thereby enhancing downstream TGF-β signaling. HBV X protein upregulates MAP1S to establish a MAP1S/Smad/TGF-β1 feedback loop promoting HCC proliferation and migration.\",\n      \"method\": \"MAP1S knockdown in vitro and in vivo, Western blot, nuclear fractionation, Co-IP, tumor growth assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined mechanistic pathway (HDAC6 degradation → MT acetylation → Smad nuclear translocation), single lab\",\n      \"pmids\": [\"39374711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDKL5 phosphorylates MAP1S at S786 and S812, regulating MAP1S binding to microtubules. MAP1S phosphomutant (S786/812A) mice show severely reduced dynein binding to microtubules, impaired dynein motility in neurons, reduced delivery of AMPA receptors in dendrites, reduced tubulin tyrosination, decreased spine density and synapses, and behavioral deficits. Expression of tubulin tyrosine kinase TTL rescues dynein motility defects, placing MAP1S phosphorylation upstream of tubulin tyrosination and dynein-mediated transport.\",\n      \"method\": \"MAP1S phosphomutant knock-in mice, microtubule co-sedimentation assay, time-lapse live imaging in neurons, dendritic cargo tracking, TTL rescue experiment, behavioral phenotyping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphomutant KI mice, co-sedimentation, live imaging, genetic rescue, multiple orthogonal methods, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.08.28.610038\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRPK directly phosphorylates MAP1S at multiple sites in a C-terminal region involved in proteolytic maturation and microtubule binding. SRPK-dependent MAP1S phosphorylation modulates the affinity of the MAP1S microtubule-binding domain for microtubules and MAP1S proteolytic processing by the Calpain-10 (CAPN10) protease. MAP1S proteolytic processing occurs progressively during neurodevelopment via a specific CAPN10 expression switch, corresponding with MAP1S acquisition of microtubule binding activity.\",\n      \"method\": \"Global phosphoproteomic screening, in vitro kinase assay, microtubule binding assays, proteolytic processing assays, developmental expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay and functional binding/processing assays, but preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.19.677315\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Alpha-tubulin is arginylated at E77 by ATE1, and loss of this arginylation (Ate1-/- cells or tubulinE77A overexpression) increases the fraction of MAP1S associated with microtubules. MAP1S knockdown rescues the reduced microtubule growth rate and increased stability seen in Ate1-/- cells to wild-type levels, demonstrating that E77 arginylation directly regulates MAP1S microtubule binding and thereby controls microtubule dynamics.\",\n      \"method\": \"Ate1 KO cells, alpha-tubulinE77A overexpression, Map1s siRNA knockdown, microtubule co-sedimentation, live-cell MT dynamics imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic models (KO, phosphomutant), functional rescue by Map1s KD, co-sedimentation, mechanistic epistasis established\",\n      \"pmids\": [\"39852692\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAP1S is a microtubule-associated protein that bridges the autophagy machinery (via direct LC3 interaction), microtubules, and mitochondria (via LRPPRC interaction) to positively regulate autophagy flux from autophagosomal biogenesis through lysosomal degradation; its stability is controlled by HDAC4-mediated deacetylation, its microtubule binding is regulated by CDKL5 phosphorylation (S786/S812) and alpha-tubulin arginylation at E77, it activates NRF2 by competing with KEAP1 for NRF2 binding (via an ETGE motif) and by promoting p62-dependent autophagic KEAP1 degradation, it interacts with RASSF1A to regulate mitotic fidelity and tumor suppression, and it modulates TLR/MyD88 and TGF-β/Smad signaling pathways, with loss-of-function in mice causing mitotic defects, accumulation of dysfunctional organelles and fibronectin, liver fibrosis, renal fibrosis, genomic instability, and reduced lifespan.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAP1S is a microtubule-associated protein that couples the microtubule cytoskeleton to autophagy, mitochondrial quality control, and mitotic fidelity [#1, #6, #4]. It binds and accumulates on stabilized microtubules through a basic C-terminal microtubule-binding domain, while a distinct C-terminal sequence drives perinuclear mitochondrial aggregation and genome destruction upon overexpression [#1]; its N-terminus is required for anchoring to microtubule-organizing centers, and loss of MAP1S disrupts spindle architecture, tubulin nucleation, microtubule dynamics, and cytokinesis, producing premature sister-chromatid separation, lagging chromosomes, and multipolar spindles [#4, #9]. In autophagy, MAP1S directly binds LC3 and recruits it to stable microtubules, and through its interaction with the mitochondria-associated protein LRPPRC it links autophagosomal biogenesis to clearance of defective mitochondria and other dysfunctional organelles [#6]. MAP1S thereby drives autophagic degradation of diverse substrates—p62-associated aggresomes, lipid droplets, fibronectin, mutant huntingtin aggregates, and MyD88—and its loss in mice causes accumulation of these cargoes, genome instability, liver and renal fibrosis, oxidative stress, and reduced lifespan [#7, #14, #15, #12, #13]. MAP1S protein stability is controlled by HDAC4, which destabilizes it via deacetylation; the polyamine spermidine depletes cytosolic HDAC4 to stabilize MAP1S and enhance autophagy, an effect genetically dependent on MAP1S [#12, #16]. MAP1S also activates NRF2 by competing with KEAP1 for NRF2 binding through an ETGE motif and by accelerating p62-dependent autophagic degradation of KEAP1 [#17]. Its microtubule binding is further tuned by post-translational inputs, including CDKL5 phosphorylation at S786/S812 that governs dynein-mediated transport and tubulin tyrosination in neurons, and alpha-tubulin arginylation at E77 by ATE1 [#20, #22]. MAP1S interacts with RASSF1A to influence microtubule hyperstabilization and chemosensitivity [#2, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the existence of MAP1S as a MAP1A/MAP1B-homologous protein and a candidate cytoskeletal adaptor, answering what gene/protein this locus encodes.\",\n      \"evidence\": \"Yeast two-hybrid against VCY2, Northern blot, in situ hybridization\",\n      \"pmids\": [\"14627543\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"VCY2 interaction never functionally validated in mammalian cells\", \"no demonstrated cytoskeletal function at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined MAP1S as a genuine microtubule-binding protein with separable functional domains, resolving how it engages microtubules versus triggering organelle/genome destruction.\",\n      \"evidence\": \"In vitro microtubule binding with purified tubulin, deletion mutagenesis, immunofluorescence in mammalian cells\",\n      \"pmids\": [\"15899810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"physiological trigger of MAGD phenotype unclear\", \"domain boundaries not validated structurally\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected MAP1S to RASSF1A-dependent microtubule hyperstabilization and to mitochondria/DNA through LRPPRC binding and intrinsic dsDNA binding, framing MAP1S as a hub linking cytoskeleton to mitochondria and genome.\",\n      \"evidence\": \"Coexpression colocalization assays; Co-IP with LRPPRC, DNA affinity chromatography, in vitro DNA binding\",\n      \"pmids\": [\"15753381\", \"15907802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of DNA binding not established (no DNase activity)\", \"single-lab interaction data without reciprocal structural mapping\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated a required mitotic role for MAP1S, answering whether the protein is functionally needed at the spindle and MTOC rather than merely binding microtubules when overexpressed.\",\n      \"evidence\": \"siRNA knockdown, time-lapse microscopy, nocodazole washout, immunofluorescence\",\n      \"pmids\": [\"17234756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular mechanism of MTOC anchoring by the N-terminus undefined\", \"link to tubulin nucleation machinery not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified MAP1S as a positive regulator of autophagy via direct LC3 binding and LRPPRC/Parkin-linked mitophagy, establishing the autophagy axis that became its central characterized function.\",\n      \"evidence\": \"Co-IP, MAP1S knockout mice, immunofluorescence, nutritive-stress assays; in vivo DEN hepatocarcinoma model\",\n      \"pmids\": [\"21262964\", \"22037873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how LC3 recruitment to microtubules couples to autophagosome maturation not mechanistically detailed\", \"relationship between mitotic and autophagic roles unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended MAP1S beyond mitosis and cancer into microtubule dynamics control, transcriptional induction during differentiation, and innate-immune/TLR signaling, broadening its functional scope.\",\n      \"evidence\": \"MT plus-end tracking and monopolar cytokinesis assays; PU.1 ChIP at the MAP1S promoter; TLR5/flagellin signaling and MyD88 autophagy assays with knockdown\",\n      \"pmids\": [\"25300793\", \"25043887\", \"24466264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking MAP1S to global MT acetylation not defined\", \"TLR/MyD88 pathway placement relies on knockdown epistasis in single labs\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified HDAC4 as a regulator of MAP1S stability and MyD88 as a direct autophagic substrate, answering how MAP1S levels are controlled and how it executes selective cargo clearance.\",\n      \"evidence\": \"Co-IP defining HDAC4-binding domain, HBD overexpression rescue, autophagy flux and aggregate assays; Co-IP with MyD88, MAP1S KO macrophage phagocytosis and LC3 colocalization\",\n      \"pmids\": [\"26540094\", \"26565030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how deacetylation destabilizes MAP1S mechanistically unclear\", \"MyD88 interaction characterized in single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established specific autophagic substrates (lipid droplets, fibronectin) whose accumulation drives organ fibrosis and shortened lifespan, linking MAP1S autophagy directly to disease-relevant pathology.\",\n      \"evidence\": \"MAP1S KD/overexpression and KO/LC3-transgenic mice, autophagy flux, substrate quantification, lifespan analysis\",\n      \"pmids\": [\"26701856\", \"26750654\", \"27236336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"selectivity mechanism distinguishing these cargoes from others not defined\", \"lysosomal degradation step mechanistically uncharacterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed MAP1S downstream of the polyamine spermidine via HDAC4-dependent stabilization, providing a pharmacological lever on MAP1S-mediated autophagy and lifespan.\",\n      \"evidence\": \"Co-IP, MAP1S KO mice, spermidine treatment with genetic epistasis, autophagy flux assays\",\n      \"pmids\": [\"28386016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how spermidine depletes cytosolic HDAC4 not resolved\", \"translational relevance beyond mouse liver unestablished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved a dual mechanism by which MAP1S activates NRF2 — ETGE-mediated competition with KEAP1 and p62-dependent autophagic KEAP1 degradation — connecting MAP1S to antioxidant defense.\",\n      \"evidence\": \"Co-IP, competitive binding assays, autophagy assays, Nrf2/p62/double KO mice in CCl4 fibrosis model\",\n      \"pmids\": [\"30873635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"relative contribution of the two parallel mechanisms not quantified\", \"ETGE-KEAP1 interface not structurally mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked RASSF1A regulation of MAP1S to KEAP1-NRF2 inactivation and cisplatin chemosensitivity, tying the early RASSF1A interaction into the autophagy/NRF2 framework.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, autophagy assays, xenograft model\",\n      \"pmids\": [\"33442234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of RASSF1A regulation of MAP1S not defined\", \"pathway placement partly inferred from prior studies\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a MAP1S/HDAC6/Smad axis whereby MAP1S-driven autophagic HDAC6 degradation increases MT acetylation and Smad nuclear translocation, implicating MAP1S in TGF-β signaling and HBV-driven HCC.\",\n      \"evidence\": \"MAP1S knockdown in vitro and in vivo, nuclear fractionation, Co-IP, tumor growth assays\",\n      \"pmids\": [\"39374711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HDAC6 as a direct autophagy substrate not biochemically confirmed\", \"single-lab pathway epistasis\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined post-translational control of MAP1S microtubule binding by CDKL5 phosphorylation, SRPK phosphorylation/CAPN10 proteolytic maturation, and alpha-tubulin E77 arginylation, explaining how MAP1S microtubule affinity and dynein-dependent transport are regulated developmentally.\",\n      \"evidence\": \"Phosphomutant knock-in mice with live imaging and TTL rescue (preprint); phosphoproteomics, in vitro kinase and processing assays (preprint); Ate1 KO cells, tubulinE77A, Map1s siRNA rescue, co-sedimentation\",\n      \"pmids\": [\"bio_10.1101_2024.08.28.610038\", \"bio_10.1101_2025.09.19.677315\", \"39852692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"two of three studies are unreviewed preprints\", \"integration of phosphorylation, proteolysis, and arginylation inputs not unified\", \"structural basis of regulated MT binding unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAP1S coordinates its distinct roles—mitotic spindle/MTOC function, selective autophagic cargo recognition, and NRF2/TGF-β signaling—into a single regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no high-resolution structure of MAP1S or its domain complexes\", \"selectivity determinants for autophagic substrates undefined\", \"no direct evidence linking the genome-instability/mitotic role to the autophagy role mechanistically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 4, 9, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 8, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 9, 22]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7, 15, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LC3\", \"LRPPRC\", \"RASSF1A\", \"HDAC4\", \"MyD88\", \"KEAP1\", \"NRF2\", \"CDKL5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}