{"gene":"GLCCI1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2011,"finding":"The GLCCI1 promoter SNPs rs37972 and rs37973 are associated with decreased GLCCI1 expression; the rs37973 variant significantly reduces luciferase reporter activity in isolated cell systems, establishing a functional link between these variants and reduced glucocorticoid-induced transcription.","method":"Luciferase reporter assay in isolated cell systems; genotype-expression correlation","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with functional validation, replicated across four independent populations, but abstract does not describe mutagenesis or reconstitution","pmids":["21991891"],"is_preprint":false},{"year":2011,"finding":"GLCCI1 protein (~60 kD) is expressed specifically in the cytoplasm of podocytes in mature mouse glomeruli; knockdown of Glcci1 in zebrafish using morpholinos causes collapsed glomeruli with foot-process effacement and disruption of the selective glomerular permeability filter, establishing a role for GLCCI1 in podocyte structure and function.","method":"RT-PCR, Western blotting, zebrafish morpholino knockdown with glomerular permeability assay","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function (morpholino knockdown) with specific cellular phenotype (foot-process effacement, glomerular permeability disruption) in zebrafish model; single lab","pmids":["21949092"],"is_preprint":false},{"year":2016,"finding":"GLCCI1 colocalizes with nephrin and synaptopodin in podocyte foot processes in vivo and in vitro. Under hyperglycemic conditions, GLCCI1 expression decreases, and this decrease is reversed by the PI3K inhibitor wortmannin, placing GLCCI1 expression downstream of the PI3K signaling pathway in podocytes.","method":"Immunofluorescence, immunoelectron microscopy, Western blotting, PI3K inhibitor (wortmannin) treatment in high-glucose podocytes and streptozotocin-induced diabetic rats","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (IEM, IF, WB, pharmacological inhibition) in single lab establishing pathway placement and subcellular localization","pmids":["27174202"],"is_preprint":false},{"year":2019,"finding":"GLCCI1 is a downstream target of the glucocorticoid receptor (GR) pathway and functions as an anti-apoptotic mediator in thymic T cells. GLCCI1 localizes to microtubules when phosphorylated; GLCCI1 knockdown in a thymocyte cell line induces apoptosis. Mechanistically, GLCCI1 binds both dynein light chain LC8-type 1 (LC8) and p21-activated kinase 1 (PAK1), inhibiting PAK1 kinase activity toward LC8 phosphorylation, which promotes LC8 dimer formation and reduces Bim expression. Transgenic mice overexpressing human GLCCI1 show enlarged thymi with increased thymocyte numbers.","method":"Co-immunoprecipitation (GLCCI1-LC8 and GLCCI1-PAK1 binding), kinase activity assay (PAK1 toward LC8), GLCCI1 knockdown in thymocyte cell line (apoptosis readout), GLCCI1 transgenic mouse (thymus size/cellularity), GLCCI1 transfection in QBI293A cells (phosphorylation/colocalization with microtubules)","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — binding confirmed by Co-IP, enzymatic activity (PAK1 kinase assay) inhibited by GLCCI1, KD phenotype, and transgenic mouse phenotype; multiple orthogonal methods in single study","pmids":["30860871"],"is_preprint":false},{"year":2021,"finding":"GLCCI1 binds directly to WDR45B (WD repeat domain 45B) and inhibits its expression, thereby suppressing autophagy and autophagosome formation in airway epithelial cells. In OVA-sensitized asthma mouse models, GLCCI1 overexpression reduces airway resistance, collagen deposition, and inflammatory cytokine production; these effects are reversed by WDR45B overexpression, establishing GLCCI1 as an upstream inhibitor of WDR45B-dependent autophagy.","method":"Co-immunoprecipitation (GLCCI1-WDR45B), GLCCI1 overexpression/knockdown in vitro and in vivo (OVA mouse model), WDR45B rescue experiments, autophagosome formation assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo epistasis rescue experiment (WDR45B reversal), single lab with two orthogonal methods","pmids":["34050597"],"is_preprint":false},{"year":2021,"finding":"GLCCI1 deficiency attenuates glucocorticoid (GC) sensitivity by shifting coactivator GRIP1 away from the glucocorticoid receptor (GR): in GLCCI1-knockout asthmatic mice and GLCCI1-silenced epithelial cells, GR and GRIP1 expression are reduced while IRF1 and IRF3 are elevated, resulting in increased GRIP1 recruitment to IRF1 and IRF3 and decreased GRIP1 recruitment to GR, thus blunting GR-mediated anti-inflammatory signaling.","method":"Co-immunoprecipitation (GRIP1:GR, GRIP1:IRF1, GRIP1:IRF3), GLCCI1-/- mouse model, GLCCI1 siRNA knockdown in Beas2B and A549 cells, Western blotting","journal":"Frontiers in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus genetic knockout and siRNA knockdown; single lab, multiple orthogonal methods","pmids":["34504850"],"is_preprint":false},{"year":2022,"finding":"An in-frame fusion of GLCCI1 exon 3 to BRAF exon 9 (GLCCI1-BRAF) produces an oncogenic fusion protein that excludes BRAF's auto-inhibitory domain but retains the kinase domain. HEK-293 cells transfected with GLCCI1-BRAF show increased phosphorylated MEK and elevated expression of EMT markers SNAI1 and ZEB1, demonstrating constitutive MAPK pathway activation.","method":"Next-generation sequencing (NGS), RT-qPCR, FISH, immunohistochemistry, Western blot (p-MEK, SNAI1, ZEB1) in transfected HEK-293 cells","journal":"European journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro transfection with functional readout (p-MEK, EMT markers), confirmed by FISH and IHC; single lab, single case","pmids":["35861986"],"is_preprint":false},{"year":2017,"finding":"Glcci1 gene and protein expression in the mouse lateral ganglionic eminence (LGE) follow a dorsal-to-ventral gradient in the ventricular zone similar to Gsx2. Glcci1 expression is reduced in Gsx2 mutants and increased in cortex after Gsx2 misexpression, placing Glcci1 downstream of the Gsx2 transcription factor. Glcci1-expressing cells co-express Ascl1 but not Sp8, identifying a specific subpopulation of LGE ventricular zone progenitors.","method":"In situ hybridization/immunofluorescence in Gsx2 mutant and Gsx2-misexpression mouse models","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic epistasis (Gsx2 mutant) with expression readout only; localization established but no functional consequence measured for GLCCI1 itself","pmids":["28744915"],"is_preprint":false},{"year":2023,"finding":"In mature mouse testis, GLCCI1 is expressed as a novel short isoform (GLCCI1-short) in spermatids, in addition to the full-length form (GLCCI1-long) in spermatocytes. GLCCI1-short binds LC8 (dynein light chain), the same anti-apoptotic target as GLCCI1-long. A luciferase reporter assay showed that β-estradiol treatment synergistically increases Glcci1-short promoter-driven luciferase activity in ERα-overexpressing cells, indicating estrogen receptor-dependent transcriptional regulation.","method":"Western blotting (isoform identification), Co-immunoprecipitation (GLCCI1-short:LC8), luciferase reporter assay (ERα-dependent promoter activation)","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus reporter assay establishing binding and transcriptional regulation; single lab, two orthogonal methods","pmids":["36468710"],"is_preprint":false},{"year":2024,"finding":"GLCCI1 directly interacts with HSP90AB1, which in turn interacts with GRP78. GLCCI1 acts as an upstream regulator of HSP90AB1 and, through it, inhibits GRP78-initiated endoplasmic reticulum stress (ERS)-induced apoptosis. GLCCI1 overexpression reduces markers of ERS-induced apoptosis (GRP78, CHOP, cleaved CASP3) in retinal ganglion cells under hyperglycemia, whereas GLCCI1 knockdown has the opposite effect.","method":"Co-immunoprecipitation (GLCCI1:HSP90AB1, HSP90AB1:GRP78), GLCCI1 overexpression/knockdown in retinal ganglion cells, in vivo mouse model of diabetic retinopathy","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding partners identified, gain- and loss-of-function with specific apoptosis markers, in vivo validation; single lab","pmids":["39496608"],"is_preprint":false},{"year":2024,"finding":"GLCCI1 deficiency in macrophages promotes NLRP3 inflammasome activation via the PI3K pathway. PI3K inhibitor LY294002 upregulates GLCCI1 in macrophages and suppresses NLRP3 activation; this effect is abrogated when macrophages lack GLCCI1 (adoptive transfer of Glcci1-/- BMDMs). MCC950 (NLRP3 inhibitor) reduces NLRP3 and ASC but does not affect GLCCI1 or p-AKT/AKT levels, placing GLCCI1 upstream of NLRP3 but downstream or parallel to PI3K/AKT.","method":"Glcci1-/- mouse model, macrophage adoptive transfer, PI3K inhibitor (LY294002) and NLRP3 inhibitor (MCC950) treatment, primary BMDM in vitro experiments, Western blotting","journal":"Chinese medical journal pulmonary and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KO + adoptive transfer) with pharmacological rescue and specific NLRP3 phenotype; single lab, multiple orthogonal approaches","pmids":["39834584"],"is_preprint":false},{"year":2025,"finding":"GLCCI1 overexpression activates the DYRK1A/FAM117B axis, which in turn activates NRF2 signaling by inhibiting NRF2 ubiquitination and degradation (inhibiting KEAP1/NRF2 axis), reversing OVA-induced mitochondrial dysfunction (ATP production, mtDNA copy number, ROS, PINK1/OPTN-mediated mitophagy) in bronchial epithelial cells and asthmatic mice.","method":"GLCCI1 overexpression in OVA mouse model and in vitro BECs, NRF2 ubiquitination assay, mitochondrial function assays (ATP, mtDNA, ROS, membrane potential), DYRK1A/FAM117B pathway modulation","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo gain-of-function with mechanistic pathway (ubiquitination assay, multiple functional readouts); single lab","pmids":["40490147"],"is_preprint":false},{"year":2026,"finding":"GLCCI1 deficiency in bronchial epithelial cells upregulates CCL5 expression via the AKT pathway, promoting eosinophil chemotaxis. Supernatant from GLCCI1-silenced BEAS-2B cells enhances eosinophil migration; inhibiting CCL5 attenuates this effect. GLCCI1-/- mice show enhanced lung eosinophilic inflammation after OVA challenge.","method":"RNA-Seq, Western blot, GLCCI1 siRNA knockdown in BEAS-2B cells, transwell eosinophil chemotaxis assay, CCL5 inhibition rescue, Glcci1-/- mouse model","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse plus siRNA KD with specific cellular phenotype (eosinophil chemotaxis), CCL5 rescue, pathway placement via AKT; single lab","pmids":["41460639"],"is_preprint":false},{"year":2026,"finding":"GLCCI1 overexpression activates the PI3K/AKT/mTOR signaling pathway and inhibits ZEB1-mediated epithelial-mesenchymal transition (EMT) in asthmatic mice and TNF-α-treated airway epithelial cells, reducing N-cadherin and Vimentin while elevating E-cadherin. ZEB1 overexpression reverses the effect of GLCCI1 overexpression, and PI3K (LY294002) or mTOR (rapamycin) inhibitors reverse GLCCI1-mediated inhibition of ZEB1-induced EMT.","method":"GLCCI1 overexpression in OVA mouse model and BEAS-2B cells (TNF-α model), ZEB1 overexpression rescue, PI3K/mTOR inhibitor treatment, Western blotting (p-PI3K, p-AKT, p-mTOR, ZEB1, E-cadherin, N-cadherin, Vimentin)","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function plus epistasis rescue (ZEB1 overexpression, pharmacological inhibitors) establishing pathway order; single lab","pmids":["41495772"],"is_preprint":false}],"current_model":"GLCCI1 is a glucocorticoid receptor (GR)-inducible cytoplasmic protein that functions as an anti-apoptotic mediator (by binding PAK1 and LC8 to inhibit pro-apoptotic signaling and Bim expression), a podocyte structural component required for glomerular filtration barrier integrity, and a modulator of glucocorticoid sensitivity in airway epithelium (by maintaining GRIP1 availability for GR rather than for competing IRF1/IRF3); it also suppresses autophagy via WDR45B, inhibits NLRP3 inflammasome activation via PI3K/AKT, reduces eosinophil recruitment by suppressing CCL5 via AKT, and protects against ER stress-induced apoptosis through HSP90AB1/GRP78, while GLCCI1 promoter variants reduce its transcriptional induction by glucocorticoids and thereby impair ICS therapeutic responses."},"narrative":{"mechanistic_narrative":"GLCCI1 (glucocorticoid-induced 1) is a glucocorticoid receptor (GR)-inducible cytoplasmic protein that acts as an anti-apoptotic and anti-inflammatory effector across multiple epithelial and immune contexts [PMID:30860871, PMID:34504850]. Mechanistically, GLCCI1 binds dynein light chain LC8 and p21-activated kinase 1 (PAK1) and inhibits PAK1 kinase activity toward LC8, promoting LC8 dimerization and suppressing pro-apoptotic Bim expression in thymocytes; its overexpression enlarges the thymus and its knockdown induces apoptosis [PMID:30860871]. GLCCI1 protects against ER stress-induced apoptosis through a direct interaction with HSP90AB1, which in turn engages GRP78 to limit GRP78/CHOP/cleaved-CASP3 signaling [PMID:39496608]. In the airway, GLCCI1 restrains pathological responses through several converging routes: it binds and downregulates WDR45B to suppress autophagosome formation [PMID:34050597], it maintains availability of the coactivator GRIP1 for GR rather than for competing IRF1/IRF3, thereby preserving GR-mediated anti-inflammatory signaling [PMID:34504850], and it acts via PI3K/AKT to restrain NLRP3 inflammasome activation in macrophages [PMID:39834584], suppress CCL5-driven eosinophil chemotaxis [PMID:41460639], and inhibit ZEB1-mediated epithelial-mesenchymal transition [PMID:41495772]. GLCCI1 also serves a structural role in podocyte foot processes, where it colocalizes with nephrin and synaptopodin and is required for glomerular filtration barrier integrity [PMID:21949092, PMID:27174202]. Common GLCCI1 promoter variants (rs37972/rs37973) reduce glucocorticoid-induced transcription of the gene and lower reporter activity, providing a functional basis for variable inhaled corticosteroid responses [PMID:21991891].","teleology":[{"year":2011,"claim":"Establishing why GLCCI1 matters clinically: promoter variants were shown to functionally reduce glucocorticoid-driven transcription, linking the locus to corticosteroid responsiveness.","evidence":"Luciferase reporter assay and genotype-expression correlation across populations","pmids":["21991891"],"confidence":"Medium","gaps":["No mutagenesis or reconstitution defining the causal nucleotide","Does not establish the downstream protein function affected by reduced expression"]},{"year":2011,"claim":"First in vivo function: GLCCI1 was localized to podocyte cytoplasm and shown by loss-of-function to be required for glomerular filtration barrier integrity, defining a structural/developmental role beyond steroid biology.","evidence":"RT-PCR/Western in mouse glomeruli; zebrafish morpholino knockdown with glomerular permeability assay","pmids":["21949092"],"confidence":"Medium","gaps":["Molecular basis of podocyte structural contribution unknown","Morpholino phenotype not confirmed with stable genetic mutant"]},{"year":2016,"claim":"Placed podocyte GLCCI1 expression within signaling: it colocalizes with nephrin/synaptopodin and its hyperglycemia-driven loss is PI3K-dependent, connecting GLCCI1 abundance to PI3K signaling.","evidence":"Immunofluorescence, immunoelectron microscopy, wortmannin treatment in high-glucose podocytes and diabetic rats","pmids":["27174202"],"confidence":"Medium","gaps":["Whether PI3K regulates GLCCI1 transcriptionally or post-translationally unresolved","No functional rescue of podocyte phenotype shown"]},{"year":2019,"claim":"Defined the core molecular mechanism: GLCCI1 binds LC8 and PAK1 and inhibits PAK1 kinase activity to promote LC8 dimerization and suppress Bim, establishing it as a GR-downstream anti-apoptotic mediator.","evidence":"Co-IP, PAK1 kinase activity assay, thymocyte knockdown, GLCCI1 transgenic mice, microtubule colocalization in QBI293A cells","pmids":["30860871"],"confidence":"High","gaps":["Structural basis of GLCCI1-PAK1/LC8 binding not determined","Phosphorylation site directing microtubule localization not mapped"]},{"year":2021,"claim":"Extended GLCCI1 to airway autophagy control: it binds and downregulates WDR45B to suppress autophagosome formation, with WDR45B rescue confirming epistasis in asthma models.","evidence":"Co-IP and WDR45B rescue in vitro and in OVA asthma mice","pmids":["34050597"],"confidence":"Medium","gaps":["How GLCCI1 represses WDR45B expression mechanistically unknown","Single lab"]},{"year":2021,"claim":"Explained GLCCI1's contribution to steroid sensitivity: it preserves GRIP1 coactivator availability for GR by limiting IRF1/IRF3 competition, mechanistically tying GLCCI1 loss to blunted anti-inflammatory signaling.","evidence":"Reciprocal Co-IP (GRIP1:GR/IRF1/IRF3), GLCCI1-/- mice and siRNA in Beas2B/A549 cells","pmids":["34504850"],"confidence":"Medium","gaps":["Direct molecular partner of GLCCI1 in this circuit not identified","Whether effect is transcriptional or via protein stability unclear"]},{"year":2023,"claim":"Showed isoform diversity with conserved function: a testis spermatid-specific GLCCI1-short isoform retains LC8 binding and is estrogen-receptor regulated, expanding the anti-apoptotic mechanism to a new tissue.","evidence":"Western isoform identification, Co-IP (GLCCI1-short:LC8), ERα-dependent luciferase reporter","pmids":["36468710"],"confidence":"Medium","gaps":["Functional role of the short isoform in spermatogenesis not tested","Whether short isoform also binds PAK1 unknown"]},{"year":2024,"claim":"Identified a chaperone-linked anti-apoptotic route: GLCCI1 interacts with HSP90AB1, which engages GRP78, to suppress ER stress-induced apoptosis in retinal ganglion cells under hyperglycemia.","evidence":"Co-IP (GLCCI1:HSP90AB1, HSP90AB1:GRP78), gain/loss-of-function in RGCs, diabetic retinopathy mouse model","pmids":["39496608"],"confidence":"Medium","gaps":["How GLCCI1 regulates HSP90AB1 (binding vs. stability) unresolved","Single lab"]},{"year":2024,"claim":"Placed GLCCI1 in inflammasome control: GLCCI1 acts downstream/parallel to PI3K/AKT to restrain NLRP3 activation in macrophages, with KO and adoptive transfer establishing necessity.","evidence":"Glcci1-/- mice, BMDM adoptive transfer, LY294002 and MCC950 treatments, Western blotting","pmids":["39834584"],"confidence":"Medium","gaps":["Direct molecular link between GLCCI1 and NLRP3 not defined","Whether GLCCI1 acts on priming or assembly unknown"]},{"year":2025,"claim":"Connected GLCCI1 to mitochondrial protection: it activates a DYRK1A/FAM117B axis that stabilizes NRF2 by inhibiting its ubiquitination, reversing OVA-induced mitochondrial dysfunction.","evidence":"Gain-of-function in OVA mice and BECs, NRF2 ubiquitination assay, mitochondrial function readouts","pmids":["40490147"],"confidence":"Medium","gaps":["Direct physical interaction of GLCCI1 with DYRK1A/FAM117B not shown","Single lab"]},{"year":2026,"claim":"Linked GLCCI1 loss to eosinophilic inflammation: deficiency upregulates CCL5 via AKT to drive eosinophil chemotaxis, with CCL5 inhibition rescuing the phenotype.","evidence":"RNA-Seq, siRNA in BEAS-2B, transwell chemotaxis, CCL5 inhibition, Glcci1-/- OVA mice","pmids":["41460639"],"confidence":"Medium","gaps":["Mechanism connecting GLCCI1 to AKT-driven CCL5 transcription unknown","Single lab"]},{"year":2026,"claim":"Defined an anti-EMT function: GLCCI1 activates PI3K/AKT/mTOR to inhibit ZEB1-mediated EMT in airway epithelium, with ZEB1 overexpression and pathway inhibitors confirming the order.","evidence":"Gain-of-function in OVA mice and TNF-α-treated BEAS-2B, ZEB1 rescue, PI3K/mTOR inhibitors, Western blotting","pmids":["41495772"],"confidence":"Medium","gaps":["Direct GLCCI1 effectors upstream of PI3K not identified","Single lab"]},{"year":null,"claim":"How GLCCI1's diverse activities — LC8/PAK1 binding, chaperone interactions, autophagy and inflammasome suppression, and multiple PI3K/AKT-linked outputs — are integrated into a single coherent biochemical function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model or defined catalytic/adaptor activity for GLCCI1","Whether the PI3K/AKT effects share a common molecular node is unknown","Direct partners in inflammasome, CCL5, and NRF2 circuits not physically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3]}],"pathway":[],"complexes":[],"partners":["LC8/DYNLL1","PAK1","WDR45B","GRIP1","HSP90AB1","GRP78"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86VQ1","full_name":"Glucocorticoid-induced transcript 1 protein","aliases":[],"length_aa":547,"mass_kda":58.0,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q86VQ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GLCCI1","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":[{"gene":"DYNLL2","stoichiometry":10.0},{"gene":"SLC23A2","stoichiometry":10.0},{"gene":"DYNLL1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/GLCCI1","total_profiled":1310},"omim":[{"mim_id":"614400","title":"GLUCOCORTICOID THERAPY, RESPONSE TO; GCTR","url":"https://www.omim.org/entry/614400"},{"mim_id":"614283","title":"GLUCOCORTICOID-INDUCED TRANSCRIPT 1; GLCCI1","url":"https://www.omim.org/entry/614283"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":31.4}],"url":"https://www.proteinatlas.org/search/GLCCI1"},"hgnc":{"alias_symbol":["GIG18","FAM117C","TSSN1"],"prev_symbol":[]},"alphafold":{"accession":"Q86VQ1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VQ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VQ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VQ1-F1-predicted_aligned_error_v6.png","plddt_mean":53.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GLCCI1","jax_strain_url":"https://www.jax.org/strain/search?query=GLCCI1"},"sequence":{"accession":"Q86VQ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86VQ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86VQ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VQ1"}},"corpus_meta":[{"pmid":"21991891","id":"PMC_21991891","title":"Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma.","date":"2011","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21991891","citation_count":265,"is_preprint":false},{"pmid":"21949092","id":"PMC_21949092","title":"Glcci1 deficiency leads to proteinuria.","date":"2011","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/21949092","citation_count":36,"is_preprint":false},{"pmid":"24673601","id":"PMC_24673601","title":"GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids.","date":"2014","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/24673601","citation_count":33,"is_preprint":false},{"pmid":"27133712","id":"PMC_27133712","title":"GLCCI1 Variation Is Associated with Asthma Susceptibility and Inhaled Corticosteroid Response in a Chinese Han Population.","date":"2016","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/27133712","citation_count":25,"is_preprint":false},{"pmid":"30860871","id":"PMC_30860871","title":"GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30860871","citation_count":22,"is_preprint":false},{"pmid":"22660954","id":"PMC_22660954","title":"GLCCI1 single nucleotide polymorphisms in pediatric nephrotic syndrome.","date":"2012","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/22660954","citation_count":17,"is_preprint":false},{"pmid":"27174202","id":"PMC_27174202","title":"GLCCI1 is a novel component associated with the PI3K signaling pathway in podocyte foot processes.","date":"2016","source":"Experimental & molecular 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and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/25843653","citation_count":9,"is_preprint":false},{"pmid":"31516081","id":"PMC_31516081","title":"GLCCI1 and STIP1 variants are associated with asthma susceptibility and inhaled corticosteroid response in a Tunisian population.","date":"2019","source":"The Journal of asthma : official journal of the Association for the Care of Asthma","url":"https://pubmed.ncbi.nlm.nih.gov/31516081","citation_count":9,"is_preprint":false},{"pmid":"34050597","id":"PMC_34050597","title":"GLCCI1 reduces collagen deposition and airway hyper-responsiveness in a mouse asthma model through binding with WD repeat domain 45B.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34050597","citation_count":9,"is_preprint":false},{"pmid":"39496608","id":"PMC_39496608","title":"GLCCI1 alleviates GRP78-initiated endoplasmic reticulum stress-induced apoptosis of retinal ganglion cells in diabetic retinopathy by upregulating and interacting with HSP90AB1.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39496608","citation_count":9,"is_preprint":false},{"pmid":"34504850","id":"PMC_34504850","title":"GLCCI1 Deficiency Induces Glucocorticoid Resistance via the Competitive Binding of IRF1:GRIP1 and IRF3:GRIP1 in Asthma.","date":"2021","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34504850","citation_count":8,"is_preprint":false},{"pmid":"35861986","id":"PMC_35861986","title":"Novel GLCCI1-BRAF fusion drives kinase signaling in a case of pheochromocytomatosis.","date":"2022","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35861986","citation_count":7,"is_preprint":false},{"pmid":"33208131","id":"PMC_33208131","title":"Effects of STIP1 and GLCCI1 polymorphisms on the risk of childhood asthma and inhaled corticosteroid response in Chinese asthmatic children.","date":"2020","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33208131","citation_count":7,"is_preprint":false},{"pmid":"34529984","id":"PMC_34529984","title":"GLCCI1 gene body methylation in peripheral blood is associated with asthma and asthma severity.","date":"2021","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34529984","citation_count":6,"is_preprint":false},{"pmid":"36468710","id":"PMC_36468710","title":"Involvement of GLCCI1 in mouse spermatogenesis.","date":"2023","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36468710","citation_count":5,"is_preprint":false},{"pmid":"40490147","id":"PMC_40490147","title":"GLCCI1 ameliorates mitochondrial dysfunction in allergic asthma mice via DYRK1A/FAM117B-dependent NRF2 activation.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40490147","citation_count":5,"is_preprint":false},{"pmid":"39834584","id":"PMC_39834584","title":"Role of GLCCI1 in inhibiting PI3K-induced NLRP3 inflammasome activation in asthma.","date":"2024","source":"Chinese medical journal pulmonary and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39834584","citation_count":5,"is_preprint":false},{"pmid":"25091946","id":"PMC_25091946","title":"Admixture of beneficial and unfavourable variants of GLCCI1 and FCER2 in Roma samples can implicate different clinical response to corticosteroids.","date":"2014","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25091946","citation_count":5,"is_preprint":false},{"pmid":"28488322","id":"PMC_28488322","title":"Impact of the genetic variants of GLCCI1 on clinical features of asthmatic patients.","date":"2017","source":"The clinical respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/28488322","citation_count":5,"is_preprint":false},{"pmid":"29224020","id":"PMC_29224020","title":"Association Between GLCCI1 Promoter Polymorphism (Rs37972) and Post-Transplant Hypertension in Renal Transplant Recipients.","date":"2017","source":"Kidney & blood pressure research","url":"https://pubmed.ncbi.nlm.nih.gov/29224020","citation_count":4,"is_preprint":false},{"pmid":"37553950","id":"PMC_37553950","title":"Glucocorticoid-Induced Transcript 1(GLCCI1) SNP rs37937 Is Associated With the Risk of Developing Allergic Rhinitis and the Response to Intranasal Corticosteroids in a Chinese Han Population.","date":"2023","source":"American journal of rhinology & allergy","url":"https://pubmed.ncbi.nlm.nih.gov/37553950","citation_count":3,"is_preprint":false},{"pmid":"29981236","id":"PMC_29981236","title":"Glucocorticoid-Induced Transcription Factor 1 (GLCCI1) Variant Impacts the Short-Term Response to Intranasal Corticosteroids in Chinese Han Patients with Seasonal Allergic Rhinitis.","date":"2018","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/29981236","citation_count":3,"is_preprint":false},{"pmid":"39198367","id":"PMC_39198367","title":"The GLCCI1/STAT3 pathway: a novel pathway involved in diabetic cognitive dysfunction and the therapeutic effect of salidroside.","date":"2024","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/39198367","citation_count":2,"is_preprint":false},{"pmid":"37157161","id":"PMC_37157161","title":"The GLCCI1 rs37973 variant and the efficacy of inhaled corticosteroids in the treatment of asthma: A meta-analysis.","date":"2023","source":"The clinical respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/37157161","citation_count":2,"is_preprint":false},{"pmid":"30937140","id":"PMC_30937140","title":"GLCCI1 rs37973 is associated with the response of adrenal hormone to inhaled corticosteroids in asthma.","date":"2019","source":"The World Allergy Organization journal","url":"https://pubmed.ncbi.nlm.nih.gov/30937140","citation_count":2,"is_preprint":false},{"pmid":"40336211","id":"PMC_40336211","title":"A Novel GLCCI1::BRAF Fusion With Independent MYC and MYCN Amplifications in Pediatric Pancreatic Acinar Cell Carcinoma.","date":"2025","source":"Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society","url":"https://pubmed.ncbi.nlm.nih.gov/40336211","citation_count":1,"is_preprint":false},{"pmid":"38348123","id":"PMC_38348123","title":"Interaction between birth characteristics and CRHR1, MC2R, NR3C1, GLCCI1 variants in the childhood lymphoblastic leukemia risk.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38348123","citation_count":0,"is_preprint":false},{"pmid":"41460639","id":"PMC_41460639","title":"GLCCI1-Deficiency Facilitates Persistent Eosinophilic Lung Inflammation in Asthma via Upregulation of CCL5.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41460639","citation_count":0,"is_preprint":false},{"pmid":"41495772","id":"PMC_41495772","title":"GLCCI1 alleviates airway remodeling in asthmatic mice by inhibiting ZEB1-mediated epithelial-mesenchymal transition.","date":"2026","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/41495772","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20754,"output_tokens":4517,"usd":0.065008,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12558,"output_tokens":4077,"usd":0.082358,"stage2_stop_reason":"end_turn"},"total_usd":0.147366,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"The GLCCI1 promoter SNPs rs37972 and rs37973 are associated with decreased GLCCI1 expression; the rs37973 variant significantly reduces luciferase reporter activity in isolated cell systems, establishing a functional link between these variants and reduced glucocorticoid-induced transcription.\",\n      \"method\": \"Luciferase reporter assay in isolated cell systems; genotype-expression correlation\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with functional validation, replicated across four independent populations, but abstract does not describe mutagenesis or reconstitution\",\n      \"pmids\": [\"21991891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GLCCI1 protein (~60 kD) is expressed specifically in the cytoplasm of podocytes in mature mouse glomeruli; knockdown of Glcci1 in zebrafish using morpholinos causes collapsed glomeruli with foot-process effacement and disruption of the selective glomerular permeability filter, establishing a role for GLCCI1 in podocyte structure and function.\",\n      \"method\": \"RT-PCR, Western blotting, zebrafish morpholino knockdown with glomerular permeability assay\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function (morpholino knockdown) with specific cellular phenotype (foot-process effacement, glomerular permeability disruption) in zebrafish model; single lab\",\n      \"pmids\": [\"21949092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GLCCI1 colocalizes with nephrin and synaptopodin in podocyte foot processes in vivo and in vitro. Under hyperglycemic conditions, GLCCI1 expression decreases, and this decrease is reversed by the PI3K inhibitor wortmannin, placing GLCCI1 expression downstream of the PI3K signaling pathway in podocytes.\",\n      \"method\": \"Immunofluorescence, immunoelectron microscopy, Western blotting, PI3K inhibitor (wortmannin) treatment in high-glucose podocytes and streptozotocin-induced diabetic rats\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (IEM, IF, WB, pharmacological inhibition) in single lab establishing pathway placement and subcellular localization\",\n      \"pmids\": [\"27174202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GLCCI1 is a downstream target of the glucocorticoid receptor (GR) pathway and functions as an anti-apoptotic mediator in thymic T cells. GLCCI1 localizes to microtubules when phosphorylated; GLCCI1 knockdown in a thymocyte cell line induces apoptosis. Mechanistically, GLCCI1 binds both dynein light chain LC8-type 1 (LC8) and p21-activated kinase 1 (PAK1), inhibiting PAK1 kinase activity toward LC8 phosphorylation, which promotes LC8 dimer formation and reduces Bim expression. Transgenic mice overexpressing human GLCCI1 show enlarged thymi with increased thymocyte numbers.\",\n      \"method\": \"Co-immunoprecipitation (GLCCI1-LC8 and GLCCI1-PAK1 binding), kinase activity assay (PAK1 toward LC8), GLCCI1 knockdown in thymocyte cell line (apoptosis readout), GLCCI1 transgenic mouse (thymus size/cellularity), GLCCI1 transfection in QBI293A cells (phosphorylation/colocalization with microtubules)\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — binding confirmed by Co-IP, enzymatic activity (PAK1 kinase assay) inhibited by GLCCI1, KD phenotype, and transgenic mouse phenotype; multiple orthogonal methods in single study\",\n      \"pmids\": [\"30860871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GLCCI1 binds directly to WDR45B (WD repeat domain 45B) and inhibits its expression, thereby suppressing autophagy and autophagosome formation in airway epithelial cells. In OVA-sensitized asthma mouse models, GLCCI1 overexpression reduces airway resistance, collagen deposition, and inflammatory cytokine production; these effects are reversed by WDR45B overexpression, establishing GLCCI1 as an upstream inhibitor of WDR45B-dependent autophagy.\",\n      \"method\": \"Co-immunoprecipitation (GLCCI1-WDR45B), GLCCI1 overexpression/knockdown in vitro and in vivo (OVA mouse model), WDR45B rescue experiments, autophagosome formation assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo epistasis rescue experiment (WDR45B reversal), single lab with two orthogonal methods\",\n      \"pmids\": [\"34050597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GLCCI1 deficiency attenuates glucocorticoid (GC) sensitivity by shifting coactivator GRIP1 away from the glucocorticoid receptor (GR): in GLCCI1-knockout asthmatic mice and GLCCI1-silenced epithelial cells, GR and GRIP1 expression are reduced while IRF1 and IRF3 are elevated, resulting in increased GRIP1 recruitment to IRF1 and IRF3 and decreased GRIP1 recruitment to GR, thus blunting GR-mediated anti-inflammatory signaling.\",\n      \"method\": \"Co-immunoprecipitation (GRIP1:GR, GRIP1:IRF1, GRIP1:IRF3), GLCCI1-/- mouse model, GLCCI1 siRNA knockdown in Beas2B and A549 cells, Western blotting\",\n      \"journal\": \"Frontiers in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus genetic knockout and siRNA knockdown; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34504850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"An in-frame fusion of GLCCI1 exon 3 to BRAF exon 9 (GLCCI1-BRAF) produces an oncogenic fusion protein that excludes BRAF's auto-inhibitory domain but retains the kinase domain. HEK-293 cells transfected with GLCCI1-BRAF show increased phosphorylated MEK and elevated expression of EMT markers SNAI1 and ZEB1, demonstrating constitutive MAPK pathway activation.\",\n      \"method\": \"Next-generation sequencing (NGS), RT-qPCR, FISH, immunohistochemistry, Western blot (p-MEK, SNAI1, ZEB1) in transfected HEK-293 cells\",\n      \"journal\": \"European journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro transfection with functional readout (p-MEK, EMT markers), confirmed by FISH and IHC; single lab, single case\",\n      \"pmids\": [\"35861986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Glcci1 gene and protein expression in the mouse lateral ganglionic eminence (LGE) follow a dorsal-to-ventral gradient in the ventricular zone similar to Gsx2. Glcci1 expression is reduced in Gsx2 mutants and increased in cortex after Gsx2 misexpression, placing Glcci1 downstream of the Gsx2 transcription factor. Glcci1-expressing cells co-express Ascl1 but not Sp8, identifying a specific subpopulation of LGE ventricular zone progenitors.\",\n      \"method\": \"In situ hybridization/immunofluorescence in Gsx2 mutant and Gsx2-misexpression mouse models\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic epistasis (Gsx2 mutant) with expression readout only; localization established but no functional consequence measured for GLCCI1 itself\",\n      \"pmids\": [\"28744915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In mature mouse testis, GLCCI1 is expressed as a novel short isoform (GLCCI1-short) in spermatids, in addition to the full-length form (GLCCI1-long) in spermatocytes. GLCCI1-short binds LC8 (dynein light chain), the same anti-apoptotic target as GLCCI1-long. A luciferase reporter assay showed that β-estradiol treatment synergistically increases Glcci1-short promoter-driven luciferase activity in ERα-overexpressing cells, indicating estrogen receptor-dependent transcriptional regulation.\",\n      \"method\": \"Western blotting (isoform identification), Co-immunoprecipitation (GLCCI1-short:LC8), luciferase reporter assay (ERα-dependent promoter activation)\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus reporter assay establishing binding and transcriptional regulation; single lab, two orthogonal methods\",\n      \"pmids\": [\"36468710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLCCI1 directly interacts with HSP90AB1, which in turn interacts with GRP78. GLCCI1 acts as an upstream regulator of HSP90AB1 and, through it, inhibits GRP78-initiated endoplasmic reticulum stress (ERS)-induced apoptosis. GLCCI1 overexpression reduces markers of ERS-induced apoptosis (GRP78, CHOP, cleaved CASP3) in retinal ganglion cells under hyperglycemia, whereas GLCCI1 knockdown has the opposite effect.\",\n      \"method\": \"Co-immunoprecipitation (GLCCI1:HSP90AB1, HSP90AB1:GRP78), GLCCI1 overexpression/knockdown in retinal ganglion cells, in vivo mouse model of diabetic retinopathy\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding partners identified, gain- and loss-of-function with specific apoptosis markers, in vivo validation; single lab\",\n      \"pmids\": [\"39496608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLCCI1 deficiency in macrophages promotes NLRP3 inflammasome activation via the PI3K pathway. PI3K inhibitor LY294002 upregulates GLCCI1 in macrophages and suppresses NLRP3 activation; this effect is abrogated when macrophages lack GLCCI1 (adoptive transfer of Glcci1-/- BMDMs). MCC950 (NLRP3 inhibitor) reduces NLRP3 and ASC but does not affect GLCCI1 or p-AKT/AKT levels, placing GLCCI1 upstream of NLRP3 but downstream or parallel to PI3K/AKT.\",\n      \"method\": \"Glcci1-/- mouse model, macrophage adoptive transfer, PI3K inhibitor (LY294002) and NLRP3 inhibitor (MCC950) treatment, primary BMDM in vitro experiments, Western blotting\",\n      \"journal\": \"Chinese medical journal pulmonary and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KO + adoptive transfer) with pharmacological rescue and specific NLRP3 phenotype; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"39834584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLCCI1 overexpression activates the DYRK1A/FAM117B axis, which in turn activates NRF2 signaling by inhibiting NRF2 ubiquitination and degradation (inhibiting KEAP1/NRF2 axis), reversing OVA-induced mitochondrial dysfunction (ATP production, mtDNA copy number, ROS, PINK1/OPTN-mediated mitophagy) in bronchial epithelial cells and asthmatic mice.\",\n      \"method\": \"GLCCI1 overexpression in OVA mouse model and in vitro BECs, NRF2 ubiquitination assay, mitochondrial function assays (ATP, mtDNA, ROS, membrane potential), DYRK1A/FAM117B pathway modulation\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo gain-of-function with mechanistic pathway (ubiquitination assay, multiple functional readouts); single lab\",\n      \"pmids\": [\"40490147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GLCCI1 deficiency in bronchial epithelial cells upregulates CCL5 expression via the AKT pathway, promoting eosinophil chemotaxis. Supernatant from GLCCI1-silenced BEAS-2B cells enhances eosinophil migration; inhibiting CCL5 attenuates this effect. GLCCI1-/- mice show enhanced lung eosinophilic inflammation after OVA challenge.\",\n      \"method\": \"RNA-Seq, Western blot, GLCCI1 siRNA knockdown in BEAS-2B cells, transwell eosinophil chemotaxis assay, CCL5 inhibition rescue, Glcci1-/- mouse model\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse plus siRNA KD with specific cellular phenotype (eosinophil chemotaxis), CCL5 rescue, pathway placement via AKT; single lab\",\n      \"pmids\": [\"41460639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GLCCI1 overexpression activates the PI3K/AKT/mTOR signaling pathway and inhibits ZEB1-mediated epithelial-mesenchymal transition (EMT) in asthmatic mice and TNF-α-treated airway epithelial cells, reducing N-cadherin and Vimentin while elevating E-cadherin. ZEB1 overexpression reverses the effect of GLCCI1 overexpression, and PI3K (LY294002) or mTOR (rapamycin) inhibitors reverse GLCCI1-mediated inhibition of ZEB1-induced EMT.\",\n      \"method\": \"GLCCI1 overexpression in OVA mouse model and BEAS-2B cells (TNF-α model), ZEB1 overexpression rescue, PI3K/mTOR inhibitor treatment, Western blotting (p-PI3K, p-AKT, p-mTOR, ZEB1, E-cadherin, N-cadherin, Vimentin)\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function plus epistasis rescue (ZEB1 overexpression, pharmacological inhibitors) establishing pathway order; single lab\",\n      \"pmids\": [\"41495772\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GLCCI1 is a glucocorticoid receptor (GR)-inducible cytoplasmic protein that functions as an anti-apoptotic mediator (by binding PAK1 and LC8 to inhibit pro-apoptotic signaling and Bim expression), a podocyte structural component required for glomerular filtration barrier integrity, and a modulator of glucocorticoid sensitivity in airway epithelium (by maintaining GRIP1 availability for GR rather than for competing IRF1/IRF3); it also suppresses autophagy via WDR45B, inhibits NLRP3 inflammasome activation via PI3K/AKT, reduces eosinophil recruitment by suppressing CCL5 via AKT, and protects against ER stress-induced apoptosis through HSP90AB1/GRP78, while GLCCI1 promoter variants reduce its transcriptional induction by glucocorticoids and thereby impair ICS therapeutic responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GLCCI1 (glucocorticoid-induced 1) is a glucocorticoid receptor (GR)-inducible cytoplasmic protein that acts as an anti-apoptotic and anti-inflammatory effector across multiple epithelial and immune contexts [#3, #5]. Mechanistically, GLCCI1 binds dynein light chain LC8 and p21-activated kinase 1 (PAK1) and inhibits PAK1 kinase activity toward LC8, promoting LC8 dimerization and suppressing pro-apoptotic Bim expression in thymocytes; its overexpression enlarges the thymus and its knockdown induces apoptosis [#3]. GLCCI1 protects against ER stress-induced apoptosis through a direct interaction with HSP90AB1, which in turn engages GRP78 to limit GRP78/CHOP/cleaved-CASP3 signaling [#9]. In the airway, GLCCI1 restrains pathological responses through several converging routes: it binds and downregulates WDR45B to suppress autophagosome formation [#4], it maintains availability of the coactivator GRIP1 for GR rather than for competing IRF1/IRF3, thereby preserving GR-mediated anti-inflammatory signaling [#5], and it acts via PI3K/AKT to restrain NLRP3 inflammasome activation in macrophages [#10], suppress CCL5-driven eosinophil chemotaxis [#12], and inhibit ZEB1-mediated epithelial-mesenchymal transition [#13]. GLCCI1 also serves a structural role in podocyte foot processes, where it colocalizes with nephrin and synaptopodin and is required for glomerular filtration barrier integrity [#1, #2]. Common GLCCI1 promoter variants (rs37972/rs37973) reduce glucocorticoid-induced transcription of the gene and lower reporter activity, providing a functional basis for variable inhaled corticosteroid responses [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing why GLCCI1 matters clinically: promoter variants were shown to functionally reduce glucocorticoid-driven transcription, linking the locus to corticosteroid responsiveness.\",\n      \"evidence\": \"Luciferase reporter assay and genotype-expression correlation across populations\",\n      \"pmids\": [\"21991891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis or reconstitution defining the causal nucleotide\", \"Does not establish the downstream protein function affected by reduced expression\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"First in vivo function: GLCCI1 was localized to podocyte cytoplasm and shown by loss-of-function to be required for glomerular filtration barrier integrity, defining a structural/developmental role beyond steroid biology.\",\n      \"evidence\": \"RT-PCR/Western in mouse glomeruli; zebrafish morpholino knockdown with glomerular permeability assay\",\n      \"pmids\": [\"21949092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of podocyte structural contribution unknown\", \"Morpholino phenotype not confirmed with stable genetic mutant\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed podocyte GLCCI1 expression within signaling: it colocalizes with nephrin/synaptopodin and its hyperglycemia-driven loss is PI3K-dependent, connecting GLCCI1 abundance to PI3K signaling.\",\n      \"evidence\": \"Immunofluorescence, immunoelectron microscopy, wortmannin treatment in high-glucose podocytes and diabetic rats\",\n      \"pmids\": [\"27174202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PI3K regulates GLCCI1 transcriptionally or post-translationally unresolved\", \"No functional rescue of podocyte phenotype shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the core molecular mechanism: GLCCI1 binds LC8 and PAK1 and inhibits PAK1 kinase activity to promote LC8 dimerization and suppress Bim, establishing it as a GR-downstream anti-apoptotic mediator.\",\n      \"evidence\": \"Co-IP, PAK1 kinase activity assay, thymocyte knockdown, GLCCI1 transgenic mice, microtubule colocalization in QBI293A cells\",\n      \"pmids\": [\"30860871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GLCCI1-PAK1/LC8 binding not determined\", \"Phosphorylation site directing microtubule localization not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended GLCCI1 to airway autophagy control: it binds and downregulates WDR45B to suppress autophagosome formation, with WDR45B rescue confirming epistasis in asthma models.\",\n      \"evidence\": \"Co-IP and WDR45B rescue in vitro and in OVA asthma mice\",\n      \"pmids\": [\"34050597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GLCCI1 represses WDR45B expression mechanistically unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Explained GLCCI1's contribution to steroid sensitivity: it preserves GRIP1 coactivator availability for GR by limiting IRF1/IRF3 competition, mechanistically tying GLCCI1 loss to blunted anti-inflammatory signaling.\",\n      \"evidence\": \"Reciprocal Co-IP (GRIP1:GR/IRF1/IRF3), GLCCI1-/- mice and siRNA in Beas2B/A549 cells\",\n      \"pmids\": [\"34504850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular partner of GLCCI1 in this circuit not identified\", \"Whether effect is transcriptional or via protein stability unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed isoform diversity with conserved function: a testis spermatid-specific GLCCI1-short isoform retains LC8 binding and is estrogen-receptor regulated, expanding the anti-apoptotic mechanism to a new tissue.\",\n      \"evidence\": \"Western isoform identification, Co-IP (GLCCI1-short:LC8), ERα-dependent luciferase reporter\",\n      \"pmids\": [\"36468710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the short isoform in spermatogenesis not tested\", \"Whether short isoform also binds PAK1 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a chaperone-linked anti-apoptotic route: GLCCI1 interacts with HSP90AB1, which engages GRP78, to suppress ER stress-induced apoptosis in retinal ganglion cells under hyperglycemia.\",\n      \"evidence\": \"Co-IP (GLCCI1:HSP90AB1, HSP90AB1:GRP78), gain/loss-of-function in RGCs, diabetic retinopathy mouse model\",\n      \"pmids\": [\"39496608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GLCCI1 regulates HSP90AB1 (binding vs. stability) unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed GLCCI1 in inflammasome control: GLCCI1 acts downstream/parallel to PI3K/AKT to restrain NLRP3 activation in macrophages, with KO and adoptive transfer establishing necessity.\",\n      \"evidence\": \"Glcci1-/- mice, BMDM adoptive transfer, LY294002 and MCC950 treatments, Western blotting\",\n      \"pmids\": [\"39834584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between GLCCI1 and NLRP3 not defined\", \"Whether GLCCI1 acts on priming or assembly unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected GLCCI1 to mitochondrial protection: it activates a DYRK1A/FAM117B axis that stabilizes NRF2 by inhibiting its ubiquitination, reversing OVA-induced mitochondrial dysfunction.\",\n      \"evidence\": \"Gain-of-function in OVA mice and BECs, NRF2 ubiquitination assay, mitochondrial function readouts\",\n      \"pmids\": [\"40490147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction of GLCCI1 with DYRK1A/FAM117B not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked GLCCI1 loss to eosinophilic inflammation: deficiency upregulates CCL5 via AKT to drive eosinophil chemotaxis, with CCL5 inhibition rescuing the phenotype.\",\n      \"evidence\": \"RNA-Seq, siRNA in BEAS-2B, transwell chemotaxis, CCL5 inhibition, Glcci1-/- OVA mice\",\n      \"pmids\": [\"41460639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting GLCCI1 to AKT-driven CCL5 transcription unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined an anti-EMT function: GLCCI1 activates PI3K/AKT/mTOR to inhibit ZEB1-mediated EMT in airway epithelium, with ZEB1 overexpression and pathway inhibitors confirming the order.\",\n      \"evidence\": \"Gain-of-function in OVA mice and TNF-α-treated BEAS-2B, ZEB1 rescue, PI3K/mTOR inhibitors, Western blotting\",\n      \"pmids\": [\"41495772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GLCCI1 effectors upstream of PI3K not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GLCCI1's diverse activities — LC8/PAK1 binding, chaperone interactions, autophagy and inflammasome suppression, and multiple PI3K/AKT-linked outputs — are integrated into a single coherent biochemical function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model or defined catalytic/adaptor activity for GLCCI1\", \"Whether the PI3K/AKT effects share a common molecular node is unknown\", \"Direct partners in inflammasome, CCL5, and NRF2 circuits not physically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LC8/DYNLL1\", \"PAK1\", \"WDR45B\", \"GRIP1\", \"HSP90AB1\", \"GRP78\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}