{"gene":"GIMAP6","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2013,"finding":"GIMAP6 interacts specifically with GABARAPL2 (an Atg8 homologue) in the cytosol; this interaction was identified by biotin tag-affinity purification and confirmed by chemical cross-linking in Jurkat T cells. Deletion of the last 10 amino acids of GIMAP6 disrupted the interaction, while the N-terminal putative Atg8-family interacting motif was not required. Upon starvation, GIMAP6 relocates to autophagosomes marked by GABARAPL2 and MAP1LC3B, and starvation leads to GIMAP6 degradation.","method":"Biotin tag-affinity purification, chemical cross-linking, deletion mutagenesis, fluorescence co-localization with autophagosomal markers, starvation assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal affinity purification, cross-linking in endogenous system, mutagenesis mapping interaction domain, live-cell localization; multiple orthogonal methods in one study, independently replicated in later work","pmids":["24204963"],"is_preprint":false},{"year":2013,"finding":"Over-expression of GIMAP6 increased endogenous GABARAPL2 protein levels in cells, but GIMAP6 over-expression did not detectably alter autophagic flux (negative finding for flux regulation).","method":"Over-expression with western blot for GABARAPL2; autophagic flux assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two distinct readouts (protein level and flux) in single lab; negative flux result explicitly stated","pmids":["24204963"],"is_preprint":false},{"year":2017,"finding":"Recombinant purified human GIMAP6 possesses both ATPase and GTPase enzymatic activity in vitro. However, the nucleotide hydrolysis activity was not required for its anti-apoptotic function in Huh-7 cells.","method":"Recombinant protein purification to homogeneity; in vitro ATPase/GTPase activity assays; functional rescue assay with hydrolysis-deficient mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic reconstitution with purified protein plus mutagenesis to separate hydrolysis from function; single lab but multiple orthogonal methods","pmids":["28381553"],"is_preprint":false},{"year":2017,"finding":"GIMAP6 is expressed specifically in CD3+ T cells in human peripheral blood. Knockdown of GIMAP6 in Jurkat cells increased apoptosis upon hydrogen peroxide, FasL, or okadaic acid treatment, and accelerated T cell activation under PMA/ionomycin. Exogenous GIMAP6 expression protected Huh-7 cells from apoptosis, establishing GIMAP6 as an anti-apoptotic protein.","method":"FACS sorting, quantitative RT-PCR, siRNA knockdown, apoptosis assays (multiple stimuli), over-expression rescue in Huh-7 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function in multiple cell systems with defined apoptotic phenotype, multiple orthogonal stimuli; replicated directionally in subsequent mouse KO work","pmids":["28381553"],"is_preprint":false},{"year":2017,"finding":"GIMAP6 knockdown in Jurkat cells reduced p65 phosphorylation at Ser-536, indicating that GIMAP6 supports NF-κB activation as part of its anti-apoptotic mechanism.","method":"siRNA knockdown, western blot for phospho-p65 (Ser-536)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single method (western blot), mechanistic link inferred from correlative phosphorylation change","pmids":["28381553"],"is_preprint":false},{"year":2018,"finding":"Conditional deletion of Gimap6 in T and B cells (CD2Cre mice) caused a 50–70% reduction in peripheral CD4+ and CD8+ T cells, establishing a requirement for GIMAP6 in peripheral T cell maintenance.","method":"Cre-mediated conditional knockout mouse model, flow cytometry of peripheral lymphocytes","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO in mice with quantified cellular phenotype; replicated directionally in the 2022 Yao et al. Gimap6-/- mouse study","pmids":["29718959"],"is_preprint":false},{"year":2018,"finding":"Gimap6-/- CD4+ T cells showed elevated MAP1LC3B (especially lipidated LC3-II), increased S405-phosphorylation of SQSTM1, increased mitochondrial/cytoplasmic volume ratio, and increased autophagosome numbers by electron microscopy, indicating disrupted autophagic flux caused by GIMAP6 loss.","method":"Western blot, electron microscopy, Cre-mediated conditional KO mouse","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal readouts (biochemical markers + ultrastructural EM) in KO mouse; independently replicated in 2022 Yao et al.","pmids":["29718959"],"is_preprint":false},{"year":2018,"finding":"Acute loss of GIMAP6 in CD4+ splenocytes (4-hydroxytamoxifen-induced ERT2Cre) increased SQSTM1 and TBK1 phosphorylation within 5 days, confirming a rapid role for GIMAP6 in autophagy regulation.","method":"Tamoxifen-inducible Cre deletion, western blot for phospho-SQSTM1 and phospho-TBK1","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible KO with time-course, two phospho-protein readouts, single lab","pmids":["29718959"],"is_preprint":false},{"year":2022,"finding":"GIMAP6 forms a complex with GABARAPL2 and GIMAP7; within this complex, GIMAP6 regulates GTPase activity. Patients with loss-of-function GIMAP6 mutations and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipid metabolism.","method":"Complex immunoprecipitation/biochemical interaction studies, GTPase activity assays, patient-derived cells, Gimap6-/- mouse model with multi-omics (lipid profiling, redox assays)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — human IEI genetics plus KO mouse with multiple orthogonal biochemical readouts (GTPase activity, autophagy markers, lipidomics, redox); replicated GIMAP6-GABARAPL2 interaction from prior work and extended it","pmids":["35551368"],"is_preprint":false},{"year":2022,"finding":"GIMAP6 expression is induced by IFN-γ and plays a critical role in antibacterial immunity, as shown in Gimap6-/- mice.","method":"IFN-γ stimulation assays, Gimap6-/- mouse infection model","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined infectious phenotype plus cytokine induction experiment; single lab, abstract-level detail","pmids":["35551368"],"is_preprint":false},{"year":2022,"finding":"Gimap6-/- mice die prematurely from microangiopathic glomerulosclerosis, attributed to GIMAP6 deficiency specifically in kidney endothelial cells.","method":"Gimap6-/- mouse model with histopathology and tissue-specific expression analysis","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined organ pathology and cell-type attribution; abstract does not detail cell-specific rescue, limiting to moderate","pmids":["35551368"],"is_preprint":false},{"year":2020,"finding":"Human patients with homozygous loss-of-function GIMAP6 variants lack GIMAP6 protein (by western blot) and exhibit accelerated lymphocyte apoptosis, establishing that GIMAP6 is required to prevent apoptosis in primary human immune cells.","method":"Whole-exome sequencing, western blot, apoptosis assays on patient-derived lymphocytes","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function with protein-level confirmation and functional assay; single case report/small cohort","pmids":["33328581"],"is_preprint":false},{"year":2026,"finding":"Loss of GIMAP6 in mice causes inflammatory vasculopathy and accelerated atherosclerosis in the absence of hyperlipidemia, leading to cardiac ischemia, myocardial infarction, heart failure, and early death, identifying GIMAP6 as a protective factor against atherosclerotic cardiovascular disease.","method":"Gimap6-/- mouse model with histopathology, cardiac function measurements; human rare variant association","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cardiovascular pathology plus human genetic data; preprint, not yet peer-reviewed","pmids":["41743988"],"is_preprint":true}],"current_model":"GIMAP6 is a small GTPase (with both GTPase and ATPase activity) expressed predominantly in CD3+ T cells that forms a cytosolic complex with GABARAPL2 and GIMAP7 to regulate GTPase activity and autophagic flux; upon starvation it relocates to autophagosomes where it is degraded, its loss disrupts autophagy and redox/PUFA-lipid homeostasis, and it exerts anti-apoptotic function (partly via NF-κB p65) and supports peripheral T cell maintenance, antibacterial immunity, and protection against inflammatory vasculopathy, with nucleotide hydrolysis activity dispensable for its anti-apoptotic role."},"narrative":{"mechanistic_narrative":"GIMAP6 is a T-cell-enriched nucleotide-binding protein that links the autophagy machinery to lymphocyte survival and immune homeostasis [PMID:28381553, PMID:35551368]. It binds the Atg8-family protein GABARAPL2 in the cytosol through its extreme C-terminus, and upon starvation relocates to GABARAPL2/MAP1LC3B-marked autophagosomes where it is itself degraded [PMID:24204963]. As part of a cytosolic complex with GABARAPL2 and GIMAP7, GIMAP6 regulates GTPase activity and is required for normal autophagic flux: its loss in CD4+ T cells produces accumulation of lipidated LC3-II, phosphorylated SQSTM1 and TBK1, and increased autophagosome numbers [PMID:29718959, PMID:35551368]. Purified GIMAP6 has intrinsic ATPase and GTPase activity, but this hydrolytic activity is dispensable for its anti-apoptotic role [PMID:28381553]. GIMAP6 acts as an anti-apoptotic factor in T cells and primary human lymphocytes, supporting NF-κB p65 activation, and is required for peripheral T-cell maintenance [PMID:28381553, PMID:29718959, PMID:33328581]. Beyond immune-cell survival, GIMAP6 deficiency disrupts redox balance and polyunsaturated fatty acid lipid metabolism, impairs IFN-γ-inducible antibacterial immunity, and causes vascular and renal pathology in mice [PMID:35551368]. Homozygous loss-of-function GIMAP6 variants in humans abolish the protein and cause accelerated lymphocyte apoptosis, defining a human immunodeficiency syndrome [PMID:35551368, PMID:33328581].","teleology":[{"year":2013,"claim":"Established the first molecular partner of GIMAP6 by showing it engages the autophagy machinery, framing the protein as autophagy-linked rather than free-standing.","evidence":"Biotin tag-affinity purification, cross-linking, deletion mapping, and starvation-induced co-localization in Jurkat T cells","pmids":["24204963"],"confidence":"High","gaps":["Functional consequence of the GABARAPL2 interaction for autophagy was not resolved (over-expression did not alter flux)","C-terminal binding determinant defined but structural basis unknown"]},{"year":2017,"claim":"Defined GIMAP6 as an enzymatically active NTPase yet showed hydrolysis is uncoupled from its cellular role, identifying its anti-apoptotic function as the key activity.","evidence":"In vitro ATPase/GTPase assays on recombinant protein plus hydrolysis-deficient rescue in Huh-7 cells; siRNA and over-expression apoptosis assays across cell types","pmids":["28381553"],"confidence":"High","gaps":["The biochemical role of nucleotide binding/hydrolysis remains undefined","Mechanistic link between GIMAP6 and NF-κB p65 phosphorylation is correlative"]},{"year":2018,"claim":"Moved GIMAP6 from cell-line correlation to an in vivo requirement, demonstrating it sustains the peripheral T-cell pool and normal autophagic flux.","evidence":"Conditional and inducible Cre knockout mice with flow cytometry, autophagy marker western blots, and electron microscopy","pmids":["29718959"],"confidence":"High","gaps":["Whether disrupted autophagy directly causes the T-cell loss versus parallel effects was not separated","Mechanism connecting GIMAP6 loss to elevated TBK1/SQSTM1 phosphorylation unclear"]},{"year":2020,"claim":"Provided human genetic validation that GIMAP6 prevents lymphocyte apoptosis in primary cells, extending the anti-apoptotic role to patients.","evidence":"Whole-exome sequencing, protein western blot, and apoptosis assays on patient-derived lymphocytes","pmids":["33328581"],"confidence":"Medium","gaps":["Small cohort/case-level evidence","Did not define the molecular pathway downstream of GIMAP6 loss in patient cells"]},{"year":2022,"claim":"Integrated the GABARAPL2-GIMAP7-GIMAP6 complex with broad physiological consequences, linking GIMAP6 to GTPase regulation, redox and PUFA-lipid metabolism, antibacterial immunity, and tissue protection.","evidence":"Complex IP and GTPase assays, patient-derived cells, and Gimap6-/- mice with lipidomics, redox assays, infection, and histopathology","pmids":["35551368"],"confidence":"High","gaps":["How GIMAP6 regulates GTPase activity within the complex mechanistically is not detailed","Causal chain from autophagy defect to lipid/redox dysregulation and to glomerulosclerosis not fully dissected"]},{"year":2026,"claim":"Expanded the protective role of GIMAP6 to cardiovascular disease, showing its loss drives inflammatory vasculopathy and atherosclerosis independent of hyperlipidemia.","evidence":"Gimap6-/- mouse histopathology and cardiac function plus human rare-variant association (preprint)","pmids":["41743988"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Cell-type and molecular mechanism driving the vasculopathy not established","Relationship to the autophagy/lipid functions of GIMAP6 unclear"]},{"year":null,"claim":"The unifying biochemical mechanism by which GIMAP6's nucleotide binding and GABARAPL2/GIMAP7 complex membership convert into autophagy control, apoptosis resistance, and lipid/redox homeostasis remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of GIMAP6 or its complex","GTPase regulatory partner/effector within the complex unidentified","Direct substrate or effector mediating anti-apoptotic activity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[2,8]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,9]}],"complexes":["GIMAP6-GIMAP7-GABARAPL2 complex"],"partners":["GABARAPL2","GIMAP7","MAP1LC3B"],"other_free_text":[]}},"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 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Deletion of the last 10 amino acids of GIMAP6 disrupted the interaction, while the N-terminal putative Atg8-family interacting motif was not required. Upon starvation, GIMAP6 relocates to autophagosomes marked by GABARAPL2 and MAP1LC3B, and starvation leads to GIMAP6 degradation.\",\n      \"method\": \"Biotin tag-affinity purification, chemical cross-linking, deletion mutagenesis, fluorescence co-localization with autophagosomal markers, starvation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal affinity purification, cross-linking in endogenous system, mutagenesis mapping interaction domain, live-cell localization; multiple orthogonal methods in one study, independently replicated in later work\",\n      \"pmids\": [\"24204963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Over-expression of GIMAP6 increased endogenous GABARAPL2 protein levels in cells, but GIMAP6 over-expression did not detectably alter autophagic flux (negative finding for flux regulation).\",\n      \"method\": \"Over-expression with western blot for GABARAPL2; autophagic flux assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two distinct readouts (protein level and flux) in single lab; negative flux result explicitly stated\",\n      \"pmids\": [\"24204963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Recombinant purified human GIMAP6 possesses both ATPase and GTPase enzymatic activity in vitro. However, the nucleotide hydrolysis activity was not required for its anti-apoptotic function in Huh-7 cells.\",\n      \"method\": \"Recombinant protein purification to homogeneity; in vitro ATPase/GTPase activity assays; functional rescue assay with hydrolysis-deficient mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic reconstitution with purified protein plus mutagenesis to separate hydrolysis from function; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28381553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GIMAP6 is expressed specifically in CD3+ T cells in human peripheral blood. Knockdown of GIMAP6 in Jurkat cells increased apoptosis upon hydrogen peroxide, FasL, or okadaic acid treatment, and accelerated T cell activation under PMA/ionomycin. Exogenous GIMAP6 expression protected Huh-7 cells from apoptosis, establishing GIMAP6 as an anti-apoptotic protein.\",\n      \"method\": \"FACS sorting, quantitative RT-PCR, siRNA knockdown, apoptosis assays (multiple stimuli), over-expression rescue in Huh-7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function in multiple cell systems with defined apoptotic phenotype, multiple orthogonal stimuli; replicated directionally in subsequent mouse KO work\",\n      \"pmids\": [\"28381553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GIMAP6 knockdown in Jurkat cells reduced p65 phosphorylation at Ser-536, indicating that GIMAP6 supports NF-κB activation as part of its anti-apoptotic mechanism.\",\n      \"method\": \"siRNA knockdown, western blot for phospho-p65 (Ser-536)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (western blot), mechanistic link inferred from correlative phosphorylation change\",\n      \"pmids\": [\"28381553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional deletion of Gimap6 in T and B cells (CD2Cre mice) caused a 50–70% reduction in peripheral CD4+ and CD8+ T cells, establishing a requirement for GIMAP6 in peripheral T cell maintenance.\",\n      \"method\": \"Cre-mediated conditional knockout mouse model, flow cytometry of peripheral lymphocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO in mice with quantified cellular phenotype; replicated directionally in the 2022 Yao et al. Gimap6-/- mouse study\",\n      \"pmids\": [\"29718959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Gimap6-/- CD4+ T cells showed elevated MAP1LC3B (especially lipidated LC3-II), increased S405-phosphorylation of SQSTM1, increased mitochondrial/cytoplasmic volume ratio, and increased autophagosome numbers by electron microscopy, indicating disrupted autophagic flux caused by GIMAP6 loss.\",\n      \"method\": \"Western blot, electron microscopy, Cre-mediated conditional KO mouse\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal readouts (biochemical markers + ultrastructural EM) in KO mouse; independently replicated in 2022 Yao et al.\",\n      \"pmids\": [\"29718959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Acute loss of GIMAP6 in CD4+ splenocytes (4-hydroxytamoxifen-induced ERT2Cre) increased SQSTM1 and TBK1 phosphorylation within 5 days, confirming a rapid role for GIMAP6 in autophagy regulation.\",\n      \"method\": \"Tamoxifen-inducible Cre deletion, western blot for phospho-SQSTM1 and phospho-TBK1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible KO with time-course, two phospho-protein readouts, single lab\",\n      \"pmids\": [\"29718959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GIMAP6 forms a complex with GABARAPL2 and GIMAP7; within this complex, GIMAP6 regulates GTPase activity. Patients with loss-of-function GIMAP6 mutations and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipid metabolism.\",\n      \"method\": \"Complex immunoprecipitation/biochemical interaction studies, GTPase activity assays, patient-derived cells, Gimap6-/- mouse model with multi-omics (lipid profiling, redox assays)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human IEI genetics plus KO mouse with multiple orthogonal biochemical readouts (GTPase activity, autophagy markers, lipidomics, redox); replicated GIMAP6-GABARAPL2 interaction from prior work and extended it\",\n      \"pmids\": [\"35551368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GIMAP6 expression is induced by IFN-γ and plays a critical role in antibacterial immunity, as shown in Gimap6-/- mice.\",\n      \"method\": \"IFN-γ stimulation assays, Gimap6-/- mouse infection model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined infectious phenotype plus cytokine induction experiment; single lab, abstract-level detail\",\n      \"pmids\": [\"35551368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Gimap6-/- mice die prematurely from microangiopathic glomerulosclerosis, attributed to GIMAP6 deficiency specifically in kidney endothelial cells.\",\n      \"method\": \"Gimap6-/- mouse model with histopathology and tissue-specific expression analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined organ pathology and cell-type attribution; abstract does not detail cell-specific rescue, limiting to moderate\",\n      \"pmids\": [\"35551368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human patients with homozygous loss-of-function GIMAP6 variants lack GIMAP6 protein (by western blot) and exhibit accelerated lymphocyte apoptosis, establishing that GIMAP6 is required to prevent apoptosis in primary human immune cells.\",\n      \"method\": \"Whole-exome sequencing, western blot, apoptosis assays on patient-derived lymphocytes\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function with protein-level confirmation and functional assay; single case report/small cohort\",\n      \"pmids\": [\"33328581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of GIMAP6 in mice causes inflammatory vasculopathy and accelerated atherosclerosis in the absence of hyperlipidemia, leading to cardiac ischemia, myocardial infarction, heart failure, and early death, identifying GIMAP6 as a protective factor against atherosclerotic cardiovascular disease.\",\n      \"method\": \"Gimap6-/- mouse model with histopathology, cardiac function measurements; human rare variant association\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cardiovascular pathology plus human genetic data; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41743988\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GIMAP6 is a small GTPase (with both GTPase and ATPase activity) expressed predominantly in CD3+ T cells that forms a cytosolic complex with GABARAPL2 and GIMAP7 to regulate GTPase activity and autophagic flux; upon starvation it relocates to autophagosomes where it is degraded, its loss disrupts autophagy and redox/PUFA-lipid homeostasis, and it exerts anti-apoptotic function (partly via NF-κB p65) and supports peripheral T cell maintenance, antibacterial immunity, and protection against inflammatory vasculopathy, with nucleotide hydrolysis activity dispensable for its anti-apoptotic role.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GIMAP6 is a T-cell-enriched nucleotide-binding protein that links the autophagy machinery to lymphocyte survival and immune homeostasis [#3, #8]. It binds the Atg8-family protein GABARAPL2 in the cytosol through its extreme C-terminus, and upon starvation relocates to GABARAPL2/MAP1LC3B-marked autophagosomes where it is itself degraded [#0]. As part of a cytosolic complex with GABARAPL2 and GIMAP7, GIMAP6 regulates GTPase activity and is required for normal autophagic flux: its loss in CD4+ T cells produces accumulation of lipidated LC3-II, phosphorylated SQSTM1 and TBK1, and increased autophagosome numbers [#6, #7, #8]. Purified GIMAP6 has intrinsic ATPase and GTPase activity, but this hydrolytic activity is dispensable for its anti-apoptotic role [#2]. GIMAP6 acts as an anti-apoptotic factor in T cells and primary human lymphocytes, supporting NF-\\u03baB p65 activation, and is required for peripheral T-cell maintenance [#3, #4, #5, #11]. Beyond immune-cell survival, GIMAP6 deficiency disrupts redox balance and polyunsaturated fatty acid lipid metabolism, impairs IFN-\\u03b3-inducible antibacterial immunity, and causes vascular and renal pathology in mice [#8, #9, #10]. Homozygous loss-of-function GIMAP6 variants in humans abolish the protein and cause accelerated lymphocyte apoptosis, defining a human immunodeficiency syndrome [#8, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the first molecular partner of GIMAP6 by showing it engages the autophagy machinery, framing the protein as autophagy-linked rather than free-standing.\",\n      \"evidence\": \"Biotin tag-affinity purification, cross-linking, deletion mapping, and starvation-induced co-localization in Jurkat T cells\",\n      \"pmids\": [\"24204963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the GABARAPL2 interaction for autophagy was not resolved (over-expression did not alter flux)\", \"C-terminal binding determinant defined but structural basis unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined GIMAP6 as an enzymatically active NTPase yet showed hydrolysis is uncoupled from its cellular role, identifying its anti-apoptotic function as the key activity.\",\n      \"evidence\": \"In vitro ATPase/GTPase assays on recombinant protein plus hydrolysis-deficient rescue in Huh-7 cells; siRNA and over-expression apoptosis assays across cell types\",\n      \"pmids\": [\"28381553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The biochemical role of nucleotide binding/hydrolysis remains undefined\", \"Mechanistic link between GIMAP6 and NF-\\u03baB p65 phosphorylation is correlative\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Moved GIMAP6 from cell-line correlation to an in vivo requirement, demonstrating it sustains the peripheral T-cell pool and normal autophagic flux.\",\n      \"evidence\": \"Conditional and inducible Cre knockout mice with flow cytometry, autophagy marker western blots, and electron microscopy\",\n      \"pmids\": [\"29718959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether disrupted autophagy directly causes the T-cell loss versus parallel effects was not separated\", \"Mechanism connecting GIMAP6 loss to elevated TBK1/SQSTM1 phosphorylation unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided human genetic validation that GIMAP6 prevents lymphocyte apoptosis in primary cells, extending the anti-apoptotic role to patients.\",\n      \"evidence\": \"Whole-exome sequencing, protein western blot, and apoptosis assays on patient-derived lymphocytes\",\n      \"pmids\": [\"33328581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small cohort/case-level evidence\", \"Did not define the molecular pathway downstream of GIMAP6 loss in patient cells\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Integrated the GABARAPL2-GIMAP7-GIMAP6 complex with broad physiological consequences, linking GIMAP6 to GTPase regulation, redox and PUFA-lipid metabolism, antibacterial immunity, and tissue protection.\",\n      \"evidence\": \"Complex IP and GTPase assays, patient-derived cells, and Gimap6-/- mice with lipidomics, redox assays, infection, and histopathology\",\n      \"pmids\": [\"35551368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GIMAP6 regulates GTPase activity within the complex mechanistically is not detailed\", \"Causal chain from autophagy defect to lipid/redox dysregulation and to glomerulosclerosis not fully dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Expanded the protective role of GIMAP6 to cardiovascular disease, showing its loss drives inflammatory vasculopathy and atherosclerosis independent of hyperlipidemia.\",\n      \"evidence\": \"Gimap6-/- mouse histopathology and cardiac function plus human rare-variant association (preprint)\",\n      \"pmids\": [\"41743988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Cell-type and molecular mechanism driving the vasculopathy not established\", \"Relationship to the autophagy/lipid functions of GIMAP6 unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying biochemical mechanism by which GIMAP6's nucleotide binding and GABARAPL2/GIMAP7 complex membership convert into autophagy control, apoptosis resistance, and lipid/redox homeostasis remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of GIMAP6 or its complex\", \"GTPase regulatory partner/effector within the complex unidentified\", \"Direct substrate or effector mediating anti-apoptotic activity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"complexes\": [\"GIMAP6-GIMAP7-GABARAPL2 complex\"],\n    \"partners\": [\"GABARAPL2\", \"GIMAP7\", \"MAP1LC3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}