{"gene":"GIMAP6","run_date":"2026-04-28T18:06:52","timeline":{"discoveries":[{"year":2013,"finding":"GIMAP6 directly interacts with GABARAPL2 (an ATG8 homologue) in the cytosol of Jurkat T cells; the interaction is disrupted by deletion of the last 10 amino acids of GIMAP6 (but not its N-terminal putative AIM motif); upon starvation, GIMAP6 re-localizes to autophagosomes marked by GABARAPL2 and MAP1LC3B and is subsequently degraded, indicating it is recruited to autophagosomes during autophagy induction; over-expression of GIMAP6 increases endogenous GABARAPL2 protein levels.","method":"Biotin tag-affinity purification, chemical cross-linking in Jurkat T cells, deletion mutagenesis, fluorescence co-localization with autophagosomal markers, starvation assay with protein degradation readout","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (affinity purification, cross-linking, mutagenesis, live-cell imaging) in a single rigorous study","pmids":["24204963"],"is_preprint":false},{"year":2017,"finding":"GIMAP6 functions as an anti-apoptotic protein in T cells: knockdown in Jurkat cells increased apoptosis upon hydrogen peroxide, FasL, or okadaic acid treatment, while exogenous GIMAP6 expression protected Huh-7 cells from apoptosis. Knockdown also accelerated T cell activation under PMA/ionomycin and reduced p65 phosphorylation at Ser-536, suggesting GIMAP6 exerts anti-apoptotic function through NF-κB activation. Purified recombinant GIMAP6 exhibited both ATPase and GTPase activity, though hydrolysis activity was not required for anti-apoptotic function.","method":"siRNA knockdown, apoptosis assays (hydrogen peroxide/FasL/okadaic acid treatment), overexpression rescue in Huh-7 cells, quantitative RT-PCR of primary CD3+ T cells, western blot for p65 phosphorylation, in vitro biochemical assay of purified recombinant protein","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro enzymatic assay, mutagenesis-equivalent rescue, and loss-of-function phenotyping","pmids":["28381553"],"is_preprint":false},{"year":2018,"finding":"Conditional knockout of Gimap6 in T and B cells (CD2Cre) in mice caused a 50–70% reduction in peripheral CD4+ and CD8+ T cells, increased lipidated LC3-II and S405-phosphorylated SQSTM1 levels, elevated mitochondrial/cytoplasmic volume ratio, and increased autophagosome numbers in CD4+ T cells, indicating GIMAP6 is required for T cell maintenance and normal autophagic flux. Acute deletion via 4-OHT treatment also increased phospho-SQSTM1 and phospho-TBK1.","method":"Cre-mediated conditional gene knockout in mice, flow cytometry, western blot, electron microscopy, 4-hydroxytamoxifen-inducible deletion system","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse model with multiple orthogonal cellular phenotype readouts replicated across two genetic deletion systems","pmids":["29718959"],"is_preprint":false},{"year":2022,"finding":"GIMAP6 forms a complex with GABARAPL2 and GIMAP7 to regulate GTPase activity. GIMAP6 deficiency (human mutations and Gimap6-/- mice) results in defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipid homeostasis. GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Gimap6-/- mice die prematurely from microangiopathic glomerulosclerosis, likely due to GIMAP6 deficiency in kidney endothelial cells.","method":"Human patient genetic analysis (inborn error of immunity), Gimap6-/- mouse model, co-immunoprecipitation/complex identification, autophagy and lipid metabolic assays, IFN-γ stimulation, histopathology","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — human disease genetics corroborated by mouse KO with multiple orthogonal mechanistic readouts (complex biochemistry, metabolomics, autophagy, pathology)","pmids":["35551368"],"is_preprint":false},{"year":2020,"finding":"Human patients homozygous for a deleterious GIMAP6 variant show absence of GIMAP6 protein, accelerated lymphocyte apoptosis, and a clinical phenotype including lymphopenia and recurrent sinopulmonary infections, establishing that biallelic loss of GIMAP6 in humans causes primary immune deficiency with defective lymphocyte survival.","method":"Whole-exome sequencing, western blot (protein absence confirmed), flow cytometry, apoptosis assays, lymphocyte activation/proliferation and cytokine release assays","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 — human loss-of-function genetics with multiple immunological assays, single-family study","pmids":["33328581"],"is_preprint":false},{"year":2021,"finding":"GAS6-AS1 lncRNA acts as a sponge for miR-24-3p to regulate GIMAP6 expression; miR-24-3p directly targets GIMAP6 mRNA, and GAS6-AS1 overexpression de-represses GIMAP6, inhibiting lung adenocarcinoma cell migration and invasion.","method":"RNA immunoprecipitation, luciferase reporter assay, RNA pull-down assay, functional rescue experiments, xenograft tumor experiments","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter and RNA pull-down confirm direct miR-24-3p:GIMAP6 interaction; functional rescue validates pathway placement","pmids":["34513660"],"is_preprint":false},{"year":2023,"finding":"lncRNA EPB41L4A-AS1 sponges miR-105-5p to promote GIMAP6 transcription in NSCLC cells; overexpression of miR-105-5p or knockdown of GIMAP6 reverses the anti-proliferative effect of EPB41L4A-AS1 overexpression, placing GIMAP6 downstream of this ceRNA axis as an anti-proliferative effector.","method":"Dual-luciferase reporter assay, RNA pull-down, subcellular fractionation, functional rescue experiments, colony formation and CCK-8 assays","journal":"Critical reviews in eukaryotic gene expression","confidence":"Medium","confidence_rationale":"Tier 2-3 — luciferase and pull-down confirm direct miR-105-5p:GIMAP6 interaction with functional rescue, single lab","pmids":["36734855"],"is_preprint":false},{"year":2026,"finding":"Loss of GIMAP6 in mice causes inflammatory vasculopathy and accelerated atherosclerosis even in the absence of hyperlipidemia, progressing to cardiac ischemia, myocardial infarction, and heart failure, revealing a protective role for GIMAP6 against atherosclerotic cardiovascular disease; rare deleterious GIMAP6 variants in humans are associated with premature severe cardiovascular disease.","method":"Gimap6 knockout mouse model, histopathology, cardiac imaging, human genetic variant analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — mouse KO with defined cardiovascular phenotype and human variant correlation, but preprint without full peer review","pmids":["41743988"],"is_preprint":true}],"current_model":"GIMAP6 is a small GTPase (with both GTPase and ATPase activities) expressed predominantly in T lymphocytes that forms a complex with GABARAPL2 and GIMAP7 to regulate autophagic flux and GTPase activity; it is recruited to autophagosomes upon starvation, is required for peripheral T cell maintenance and normal autophagy in vivo, exerts anti-apoptotic function in T cells (at least partly through NF-κB/p65 signaling), is induced by IFN-γ to support antibacterial immunity, regulates PUFA-containing lipid and redox homeostasis, and protects against inflammatory vasculopathy and atherosclerosis, with biallelic human loss-of-function mutations causing a primary immune deficiency and premature cardiovascular disease."},"narrative":{"teleology":[{"year":2013,"claim":"Identifying a direct GIMAP6–GABARAPL2 interaction and starvation-induced autophagosomal recruitment established GIMAP6 as a participant in the autophagy machinery, answering how a lymphocyte GTPase connects to vesicular degradation.","evidence":"Biotin-tag affinity purification, chemical cross-linking, deletion mutagenesis, and fluorescence co-localization with autophagosomal markers in Jurkat T cells","pmids":["24204963"],"confidence":"High","gaps":["The C-terminal interaction domain was mapped by deletion but no structural model of the GIMAP6–GABARAPL2 interface exists","Whether GIMAP6 promotes autophagosome biogenesis or acts at a later fusion/maturation step was unresolved","In vivo relevance of the interaction was not tested"]},{"year":2017,"claim":"Demonstrating that GIMAP6 has dual GTPase/ATPase activity yet protects T cells from apoptosis independently of hydrolysis resolved the question of whether its enzymatic function underlies its pro-survival role, and linked it to NF-κB signaling.","evidence":"In vitro enzymatic assays on purified recombinant protein, siRNA knockdown with multiple apoptotic stimuli in Jurkat cells, overexpression rescue in Huh-7 cells, and phospho-p65 western blots","pmids":["28381553"],"confidence":"High","gaps":["The mechanism by which GIMAP6 activates NF-κB/p65 independently of GTPase activity was not defined","Whether autophagy and anti-apoptotic functions are mechanistically linked or independent pathways was unclear"]},{"year":2018,"claim":"Conditional Gimap6 deletion in mouse lymphocytes proved the gene is essential for peripheral T cell homeostasis and normal autophagic flux in vivo, translating earlier cell-line observations into a physiological context.","evidence":"CD2-Cre and tamoxifen-inducible conditional knockout mice with flow cytometry, western blot for LC3-II/phospho-SQSTM1/phospho-TBK1, and electron microscopy","pmids":["29718959"],"confidence":"High","gaps":["Relative contributions of autophagy block versus apoptosis sensitivity to T cell loss were not disentangled","Non-lymphocyte roles of GIMAP6 were not explored"]},{"year":2020,"claim":"Identification of biallelic GIMAP6 loss-of-function in human patients with lymphopenia and recurrent infections established GIMAP6 deficiency as a cause of primary immune deficiency, validating mouse findings in humans.","evidence":"Whole-exome sequencing, protein absence by western blot, apoptosis and lymphocyte function assays in patient cells","pmids":["33328581"],"confidence":"Medium","gaps":["Single-family study; replication in independent kindreds was needed","Downstream molecular pathway disrupted in patient lymphocytes was not characterized"]},{"year":2022,"claim":"Discovery of the GIMAP6–GABARAPL2–GIMAP7 ternary complex and IFN-γ-driven induction, together with defects in autophagy, redox regulation, and PUFA-lipid homeostasis in GIMAP6-deficient cells and mice, unified the autophagy, metabolic, and immune functions into a single framework and revealed a non-lymphocyte role in kidney endothelium.","evidence":"Human patient genetics and Gimap6−/− mice with co-immunoprecipitation, metabolomics, autophagy assays, IFN-γ stimulation, and renal histopathology","pmids":["35551368"],"confidence":"High","gaps":["How the ternary complex regulates GTPase activity at a structural level is unknown","Whether the lipid-homeostasis defect is a direct consequence of impaired autophagy or an independent function of GIMAP6 is unresolved","The mechanism linking GIMAP6 to endothelial cell pathology was not defined"]},{"year":2023,"claim":"Placement of GIMAP6 downstream of two independent ceRNA axes (GAS6-AS1/miR-24-3p and EPB41L4A-AS1/miR-105-5p) in lung adenocarcinoma cells defined post-transcriptional regulation of GIMAP6 and suggested a growth-suppressive role outside the immune compartment.","evidence":"Dual-luciferase reporters, RNA pull-down, functional rescue, and proliferation assays in NSCLC cell lines","pmids":["34513660","36734855"],"confidence":"Medium","gaps":["ceRNA sponge mechanisms have limited in vivo validation","Whether GIMAP6's tumor-suppressive effect operates through autophagy or a distinct pathway is unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the GIMAP6–GABARAPL2–GIMAP7 complex, whether the autophagy and anti-apoptotic functions are mechanistically separable, the direct molecular link between GIMAP6 and lipid/redox homeostasis, and the cell-type-specific contributions (lymphocytes vs. endothelium) to cardiovascular disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of GIMAP6 or its complexes","Relative contribution of autophagy versus anti-apoptotic signaling to lymphocyte and vascular phenotypes is unresolved","Endothelial-specific conditional knockout has not been reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4]}],"complexes":["GIMAP6–GABARAPL2–GIMAP7"],"partners":["GABARAPL2","GIMAP7","RELA"],"other_free_text":[]},"mechanistic_narrative":"GIMAP6 is a lymphocyte-enriched GTPase that safeguards peripheral T cell survival and vascular integrity by coordinating autophagy, redox balance, and anti-apoptotic signaling. It forms a ternary complex with GABARAPL2 and GIMAP7, is recruited to autophagosomes upon starvation, and is required for normal autophagic flux; conditional deletion in mice causes accumulation of lipidated LC3-II and phospho-SQSTM1, elevated mitochondrial mass, and a 50–70% reduction in peripheral T cells [PMID:24204963, PMID:29718959, PMID:35551368]. Recombinant GIMAP6 possesses both GTPase and ATPase activity and protects T cells from apoptosis through a mechanism involving NF-κB/p65 phosphorylation, independent of its hydrolytic activity [PMID:28381553]. Biallelic loss-of-function mutations in human GIMAP6 cause a primary immune deficiency characterized by lymphopenia and recurrent infections, and GIMAP6 deficiency drives inflammatory vasculopathy and accelerated atherosclerosis in mice [PMID:33328581, PMID:35551368]."},"prefetch_data":{"uniprot":{"accession":"Q6P9H5","full_name":"GTPase IMAP family member 6","aliases":["Immunity-associated nucleotide 2 protein","IAN-2","hIAN2","Immunity-associated nucleotide 6 protein","IAN-6","hIAN6"],"length_aa":292,"mass_kda":32.9,"function":"","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q6P9H5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GIMAP6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GIMAP6","total_profiled":1310},"omim":[{"mim_id":"616960","title":"GTPase, IMAP FAMILY, MEMBER 6; GIMAP6","url":"https://www.omim.org/entry/616960"},{"mim_id":"607452","title":"GABA-A RECEPTOR-ASSOCIATED PROTEIN-LIKE PROTEIN 2; GABARAPL2","url":"https://www.omim.org/entry/607452"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":60.3}],"url":"https://www.proteinatlas.org/search/GIMAP6"},"hgnc":{"alias_symbol":["FLJ22690","IAN6"],"prev_symbol":[]},"alphafold":{"accession":"Q6P9H5","domains":[{"cath_id":"3.40.50.300","chopping":"39-233","consensus_level":"high","plddt":95.4718,"start":39,"end":233}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P9H5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P9H5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P9H5-F1-predicted_aligned_error_v6.png","plddt_mean":86.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GIMAP6","jax_strain_url":"https://www.jax.org/strain/search?query=GIMAP6"},"sequence":{"accession":"Q6P9H5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P9H5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P9H5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P9H5"}},"corpus_meta":[{"pmid":"31952466","id":"PMC_31952466","title":"Identification of biomarkers in common chronic lung diseases by co-expression networks and drug-target interactions analysis.","date":"2020","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/31952466","citation_count":37,"is_preprint":false},{"pmid":"18462827","id":"PMC_18462827","title":"Dysregulation of GIMAP genes in non-small cell lung cancer.","date":"2008","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/18462827","citation_count":33,"is_preprint":false},{"pmid":"33221412","id":"PMC_33221412","title":"Arabidopsis immune-associated nucleotide-binding genes repress heat tolerance at the reproductive stage by inhibiting the unfolded protein response and promoting cell death.","date":"2020","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/33221412","citation_count":28,"is_preprint":false},{"pmid":"29910823","id":"PMC_29910823","title":"Network-Based Predictors of Progression in Head and Neck Squamous Cell Carcinoma.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29910823","citation_count":26,"is_preprint":false},{"pmid":"24204963","id":"PMC_24204963","title":"The immune system GTPase GIMAP6 interacts with the Atg8 homologue GABARAPL2 and is recruited to autophagosomes.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24204963","citation_count":25,"is_preprint":false},{"pmid":"24930699","id":"PMC_24930699","title":"Expression of genes associated with cholesterol and lipid metabolism identified as a novel pathway in the early pathogenesis of Mycobacterium avium subspecies paratuberculosis-infection in cattle.","date":"2014","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/24930699","citation_count":25,"is_preprint":false},{"pmid":"35711463","id":"PMC_35711463","title":"Identification of Biomarkers Associated With CD4+ T-Cell Infiltration With Gene Coexpression Network in Dermatomyositis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35711463","citation_count":20,"is_preprint":false},{"pmid":"29183316","id":"PMC_29183316","title":"RNA sequencing reveals candidate genes and polymorphisms related to sperm DNA integrity in testis tissue from boars.","date":"2017","source":"BMC veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/29183316","citation_count":18,"is_preprint":false},{"pmid":"27667392","id":"PMC_27667392","title":"Dysregulation of GTPase IMAP family members in hepatocellular cancer.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27667392","citation_count":18,"is_preprint":false},{"pmid":"28381553","id":"PMC_28381553","title":"Functional and biochemical characterization of a T cell-associated anti-apoptotic protein, GIMAP6.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28381553","citation_count":16,"is_preprint":false},{"pmid":"32523132","id":"PMC_32523132","title":"Transcriptomic study in women with trisomy 21 identifies a possible role of the GTPases of the immunity-associated proteins (GIMAP) in the protection of breast cancer.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32523132","citation_count":16,"is_preprint":false},{"pmid":"29718959","id":"PMC_29718959","title":"GIMAP6 is required for T cell maintenance and efficient autophagy in mice.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29718959","citation_count":15,"is_preprint":false},{"pmid":"35551368","id":"PMC_35551368","title":"GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans.","date":"2022","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35551368","citation_count":14,"is_preprint":false},{"pmid":"34513660","id":"PMC_34513660","title":"GAS6-AS1 Overexpression Increases GIMAP6 Expression and Inhibits Lung Adenocarcinoma Progression by Sponging miR-24-3p.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34513660","citation_count":13,"is_preprint":false},{"pmid":"33328581","id":"PMC_33328581","title":"A human case of GIMAP6 deficiency: a novel primary immune deficiency.","date":"2020","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/33328581","citation_count":11,"is_preprint":false},{"pmid":"36815102","id":"PMC_36815102","title":"Longitudinal Epigenome-Wide Analysis of Kidney Transplant Recipients Pretransplant and Posttransplant.","date":"2022","source":"Kidney international reports","url":"https://pubmed.ncbi.nlm.nih.gov/36815102","citation_count":11,"is_preprint":false},{"pmid":"35280857","id":"PMC_35280857","title":"Identification of Signature Genes and Characterizations of Tumor Immune Microenvironment and Tumor Purity in Lung Adenocarcinoma Based on Machine Learning.","date":"2022","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35280857","citation_count":11,"is_preprint":false},{"pmid":"28630090","id":"PMC_28630090","title":"T Cell Transcriptomes from Paroxysmal Nocturnal Hemoglobinuria Patients Reveal Novel Signaling Pathways.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28630090","citation_count":11,"is_preprint":false},{"pmid":"33358908","id":"PMC_33358908","title":"The molecular basis of gender disparities in smoking lung cancer patients.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33358908","citation_count":8,"is_preprint":false},{"pmid":"36734855","id":"PMC_36734855","title":"IncRNA EPB41L4A-AS1 Mitigates the Proliferation of Non-Small-Cell Lung Cancer Cells through the miR-105-5p/GIMAP6 Axis.","date":"2023","source":"Critical reviews in eukaryotic gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/36734855","citation_count":5,"is_preprint":false},{"pmid":"39889200","id":"PMC_39889200","title":"Identification of potential biomarkers associated with cuproptosis and immune microenvironment analysis in acute myocardial infarction: A diagnostic accuracy study.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39889200","citation_count":5,"is_preprint":false},{"pmid":"40133574","id":"PMC_40133574","title":"Uncovering Hippo pathway-related biomarkers in acute myocardial infarction via scRNA-seq binding transcriptomics.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40133574","citation_count":3,"is_preprint":false},{"pmid":"41743988","id":"PMC_41743988","title":"Immunoregulatory gene GIMAP6 suppresses lethal atherosclerotic vasculopathy and ischemic heart failure.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41743988","citation_count":0,"is_preprint":false},{"pmid":"41074150","id":"PMC_41074150","title":"Decoding IBD progression: a dynamic biomarker atlas for personalized disease stratification.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41074150","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14623,"output_tokens":2453,"usd":0.040332},"stage2":{"model":"claude-opus-4-6","input_tokens":5744,"output_tokens":2198,"usd":0.125505},"total_usd":0.165837,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"GIMAP6 directly interacts with GABARAPL2 (an ATG8 homologue) in the cytosol of Jurkat T cells; the interaction is disrupted by deletion of the last 10 amino acids of GIMAP6 (but not its N-terminal putative AIM motif); upon starvation, GIMAP6 re-localizes to autophagosomes marked by GABARAPL2 and MAP1LC3B and is subsequently degraded, indicating it is recruited to autophagosomes during autophagy induction; over-expression of GIMAP6 increases endogenous GABARAPL2 protein levels.\",\n      \"method\": \"Biotin tag-affinity purification, chemical cross-linking in Jurkat T cells, deletion mutagenesis, fluorescence co-localization with autophagosomal markers, starvation assay with protein degradation readout\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (affinity purification, cross-linking, mutagenesis, live-cell imaging) in a single rigorous study\",\n      \"pmids\": [\"24204963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GIMAP6 functions as an anti-apoptotic protein in T cells: knockdown in Jurkat cells increased apoptosis upon hydrogen peroxide, FasL, or okadaic acid treatment, while exogenous GIMAP6 expression protected Huh-7 cells from apoptosis. Knockdown also accelerated T cell activation under PMA/ionomycin and reduced p65 phosphorylation at Ser-536, suggesting GIMAP6 exerts anti-apoptotic function through NF-κB activation. Purified recombinant GIMAP6 exhibited both ATPase and GTPase activity, though hydrolysis activity was not required for anti-apoptotic function.\",\n      \"method\": \"siRNA knockdown, apoptosis assays (hydrogen peroxide/FasL/okadaic acid treatment), overexpression rescue in Huh-7 cells, quantitative RT-PCR of primary CD3+ T cells, western blot for p65 phosphorylation, in vitro biochemical assay of purified recombinant protein\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro enzymatic assay, mutagenesis-equivalent rescue, and loss-of-function phenotyping\",\n      \"pmids\": [\"28381553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional knockout of Gimap6 in T and B cells (CD2Cre) in mice caused a 50–70% reduction in peripheral CD4+ and CD8+ T cells, increased lipidated LC3-II and S405-phosphorylated SQSTM1 levels, elevated mitochondrial/cytoplasmic volume ratio, and increased autophagosome numbers in CD4+ T cells, indicating GIMAP6 is required for T cell maintenance and normal autophagic flux. Acute deletion via 4-OHT treatment also increased phospho-SQSTM1 and phospho-TBK1.\",\n      \"method\": \"Cre-mediated conditional gene knockout in mice, flow cytometry, western blot, electron microscopy, 4-hydroxytamoxifen-inducible deletion system\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse model with multiple orthogonal cellular phenotype readouts replicated across two genetic deletion systems\",\n      \"pmids\": [\"29718959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GIMAP6 forms a complex with GABARAPL2 and GIMAP7 to regulate GTPase activity. GIMAP6 deficiency (human mutations and Gimap6-/- mice) results in defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipid homeostasis. GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Gimap6-/- mice die prematurely from microangiopathic glomerulosclerosis, likely due to GIMAP6 deficiency in kidney endothelial cells.\",\n      \"method\": \"Human patient genetic analysis (inborn error of immunity), Gimap6-/- mouse model, co-immunoprecipitation/complex identification, autophagy and lipid metabolic assays, IFN-γ stimulation, histopathology\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — human disease genetics corroborated by mouse KO with multiple orthogonal mechanistic readouts (complex biochemistry, metabolomics, autophagy, pathology)\",\n      \"pmids\": [\"35551368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human patients homozygous for a deleterious GIMAP6 variant show absence of GIMAP6 protein, accelerated lymphocyte apoptosis, and a clinical phenotype including lymphopenia and recurrent sinopulmonary infections, establishing that biallelic loss of GIMAP6 in humans causes primary immune deficiency with defective lymphocyte survival.\",\n      \"method\": \"Whole-exome sequencing, western blot (protein absence confirmed), flow cytometry, apoptosis assays, lymphocyte activation/proliferation and cytokine release assays\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function genetics with multiple immunological assays, single-family study\",\n      \"pmids\": [\"33328581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GAS6-AS1 lncRNA acts as a sponge for miR-24-3p to regulate GIMAP6 expression; miR-24-3p directly targets GIMAP6 mRNA, and GAS6-AS1 overexpression de-represses GIMAP6, inhibiting lung adenocarcinoma cell migration and invasion.\",\n      \"method\": \"RNA immunoprecipitation, luciferase reporter assay, RNA pull-down assay, functional rescue experiments, xenograft tumor experiments\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter and RNA pull-down confirm direct miR-24-3p:GIMAP6 interaction; functional rescue validates pathway placement\",\n      \"pmids\": [\"34513660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"lncRNA EPB41L4A-AS1 sponges miR-105-5p to promote GIMAP6 transcription in NSCLC cells; overexpression of miR-105-5p or knockdown of GIMAP6 reverses the anti-proliferative effect of EPB41L4A-AS1 overexpression, placing GIMAP6 downstream of this ceRNA axis as an anti-proliferative effector.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA pull-down, subcellular fractionation, functional rescue experiments, colony formation and CCK-8 assays\",\n      \"journal\": \"Critical reviews in eukaryotic gene expression\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — luciferase and pull-down confirm direct miR-105-5p:GIMAP6 interaction with functional rescue, single lab\",\n      \"pmids\": [\"36734855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of GIMAP6 in mice causes inflammatory vasculopathy and accelerated atherosclerosis even in the absence of hyperlipidemia, progressing to cardiac ischemia, myocardial infarction, and heart failure, revealing a protective role for GIMAP6 against atherosclerotic cardiovascular disease; rare deleterious GIMAP6 variants in humans are associated with premature severe cardiovascular disease.\",\n      \"method\": \"Gimap6 knockout mouse model, histopathology, cardiac imaging, human genetic variant analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mouse KO with defined cardiovascular phenotype and human variant correlation, but preprint without full peer review\",\n      \"pmids\": [\"41743988\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GIMAP6 is a small GTPase (with both GTPase and ATPase activities) expressed predominantly in T lymphocytes that forms a complex with GABARAPL2 and GIMAP7 to regulate autophagic flux and GTPase activity; it is recruited to autophagosomes upon starvation, is required for peripheral T cell maintenance and normal autophagy in vivo, exerts anti-apoptotic function in T cells (at least partly through NF-κB/p65 signaling), is induced by IFN-γ to support antibacterial immunity, regulates PUFA-containing lipid and redox homeostasis, and protects against inflammatory vasculopathy and atherosclerosis, with biallelic human loss-of-function mutations causing a primary immune deficiency and premature cardiovascular disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GIMAP6 is a lymphocyte-enriched GTPase that safeguards peripheral T cell survival and vascular integrity by coordinating autophagy, redox balance, and anti-apoptotic signaling. It forms a ternary complex with GABARAPL2 and GIMAP7, is recruited to autophagosomes upon starvation, and is required for normal autophagic flux; conditional deletion in mice causes accumulation of lipidated LC3-II and phospho-SQSTM1, elevated mitochondrial mass, and a 50–70% reduction in peripheral T cells [PMID:24204963, PMID:29718959, PMID:35551368]. Recombinant GIMAP6 possesses both GTPase and ATPase activity and protects T cells from apoptosis through a mechanism involving NF-κB/p65 phosphorylation, independent of its hydrolytic activity [PMID:28381553]. Biallelic loss-of-function mutations in human GIMAP6 cause a primary immune deficiency characterized by lymphopenia and recurrent infections, and GIMAP6 deficiency drives inflammatory vasculopathy and accelerated atherosclerosis in mice [PMID:33328581, PMID:35551368].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying a direct GIMAP6–GABARAPL2 interaction and starvation-induced autophagosomal recruitment established GIMAP6 as a participant in the autophagy machinery, answering how a lymphocyte GTPase connects to vesicular degradation.\",\n      \"evidence\": \"Biotin-tag affinity purification, chemical cross-linking, deletion mutagenesis, and fluorescence co-localization with autophagosomal markers in Jurkat T cells\",\n      \"pmids\": [\"24204963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The C-terminal interaction domain was mapped by deletion but no structural model of the GIMAP6–GABARAPL2 interface exists\",\n        \"Whether GIMAP6 promotes autophagosome biogenesis or acts at a later fusion/maturation step was unresolved\",\n        \"In vivo relevance of the interaction was not tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that GIMAP6 has dual GTPase/ATPase activity yet protects T cells from apoptosis independently of hydrolysis resolved the question of whether its enzymatic function underlies its pro-survival role, and linked it to NF-κB signaling.\",\n      \"evidence\": \"In vitro enzymatic assays on purified recombinant protein, siRNA knockdown with multiple apoptotic stimuli in Jurkat cells, overexpression rescue in Huh-7 cells, and phospho-p65 western blots\",\n      \"pmids\": [\"28381553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The mechanism by which GIMAP6 activates NF-κB/p65 independently of GTPase activity was not defined\",\n        \"Whether autophagy and anti-apoptotic functions are mechanistically linked or independent pathways was unclear\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional Gimap6 deletion in mouse lymphocytes proved the gene is essential for peripheral T cell homeostasis and normal autophagic flux in vivo, translating earlier cell-line observations into a physiological context.\",\n      \"evidence\": \"CD2-Cre and tamoxifen-inducible conditional knockout mice with flow cytometry, western blot for LC3-II/phospho-SQSTM1/phospho-TBK1, and electron microscopy\",\n      \"pmids\": [\"29718959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contributions of autophagy block versus apoptosis sensitivity to T cell loss were not disentangled\",\n        \"Non-lymphocyte roles of GIMAP6 were not explored\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of biallelic GIMAP6 loss-of-function in human patients with lymphopenia and recurrent infections established GIMAP6 deficiency as a cause of primary immune deficiency, validating mouse findings in humans.\",\n      \"evidence\": \"Whole-exome sequencing, protein absence by western blot, apoptosis and lymphocyte function assays in patient cells\",\n      \"pmids\": [\"33328581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-family study; replication in independent kindreds was needed\",\n        \"Downstream molecular pathway disrupted in patient lymphocytes was not characterized\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of the GIMAP6–GABARAPL2–GIMAP7 ternary complex and IFN-γ-driven induction, together with defects in autophagy, redox regulation, and PUFA-lipid homeostasis in GIMAP6-deficient cells and mice, unified the autophagy, metabolic, and immune functions into a single framework and revealed a non-lymphocyte role in kidney endothelium.\",\n      \"evidence\": \"Human patient genetics and Gimap6−/− mice with co-immunoprecipitation, metabolomics, autophagy assays, IFN-γ stimulation, and renal histopathology\",\n      \"pmids\": [\"35551368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the ternary complex regulates GTPase activity at a structural level is unknown\",\n        \"Whether the lipid-homeostasis defect is a direct consequence of impaired autophagy or an independent function of GIMAP6 is unresolved\",\n        \"The mechanism linking GIMAP6 to endothelial cell pathology was not defined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placement of GIMAP6 downstream of two independent ceRNA axes (GAS6-AS1/miR-24-3p and EPB41L4A-AS1/miR-105-5p) in lung adenocarcinoma cells defined post-transcriptional regulation of GIMAP6 and suggested a growth-suppressive role outside the immune compartment.\",\n      \"evidence\": \"Dual-luciferase reporters, RNA pull-down, functional rescue, and proliferation assays in NSCLC cell lines\",\n      \"pmids\": [\"34513660\", \"36734855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ceRNA sponge mechanisms have limited in vivo validation\",\n        \"Whether GIMAP6's tumor-suppressive effect operates through autophagy or a distinct pathway is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the GIMAP6–GABARAPL2–GIMAP7 complex, whether the autophagy and anti-apoptotic functions are mechanistically separable, the direct molecular link between GIMAP6 and lipid/redox homeostasis, and the cell-type-specific contributions (lymphocytes vs. endothelium) to cardiovascular disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of GIMAP6 or its complexes\",\n        \"Relative contribution of autophagy versus anti-apoptotic signaling to lymphocyte and vascular phenotypes is unresolved\",\n        \"Endothelial-specific conditional knockout has not been reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"GIMAP6–GABARAPL2–GIMAP7\"\n    ],\n    \"partners\": [\n      \"GABARAPL2\",\n      \"GIMAP7\",\n      \"RELA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}