{"gene":"RINT1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2000,"finding":"RINT-1 was identified as a novel Rad50-interacting protein via yeast two-hybrid screen using the C-terminal region of human Rad50 as bait. The conserved central and C-terminal regions of RINT-1 are required for interaction with Rad50. RINT-1 specifically binds Rad50 only during late S and G2/M phases. Expression of N-terminally truncated RINT-1 in MCF-7 cells produced a defective radiation-induced G2/M checkpoint.","method":"Yeast two-hybrid screen, co-immunoprecipitation, cell cycle phase analysis, truncation mutant expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus truncation mutant functional assay in a single lab, two orthogonal methods","pmids":["11096100"],"is_preprint":false},{"year":2006,"finding":"RINT-1 regulates the localization and entry of ZW10 into the syntaxin 18 (STX18) SNARE complex at the ER. The N-terminal region of RINT-1 mediates interaction with ZW10. Overexpression of RINT-1 N-terminus caused ZW10 redistribution and blocked ER-to-Golgi transport. Knockdown of RINT-1 reduced ZW10 association with syntaxin 18 and redistributed ZW10, while knockdown of ZW10 did not displace RINT-1 from the syntaxin 18 complex, establishing RINT-1 as the linker between ZW10 and the STX18 SNARE complex.","method":"siRNA knockdown, overexpression of truncation mutants, co-immunoprecipitation, Golgi morphology imaging, ER-to-Golgi transport assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdown epistasis, co-IP, transport assay, and localization imaging with functional consequence, multiple orthogonal methods in one study","pmids":["16571679"],"is_preprint":false},{"year":2006,"finding":"p130 (Rb-related protein) interacts specifically with RINT-1, and both p130 and RINT-1 are essential for telomere length control. A complex of p130–RINT-1–Rad50 was proposed to block telomerase-independent (recombination-based) telomere lengthening in normal cells.","method":"Co-immunoprecipitation, genetic loss-of-function (siRNA/dominant-negative), telomere length assays","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional telomere assay in single lab, two orthogonal methods","pmids":["16600870"],"is_preprint":false},{"year":2007,"finding":"RINT-1 functions downstream of or in a parallel pathway to Rab6 for Golgi homeostasis: epistatic siRNA depletion showed that Rab6 depletion inhibited Golgi disruption caused by RINT-1 (or ZW10) knockdown. Dominant-negative GDP-Rab6 suppressed ZW10-knockdown-induced Golgi disruption. A C-terminal fragment of Bicaudal D (linker between Rab6 and dynactin/dynein) suppressed ZW10 but not COG knockdown-induced Golgi disruption, placing RINT-1/ZW10 upstream of Rab6-dynein axis.","method":"siRNA epistasis, dominant-negative expression, Golgi morphology imaging, ERGIC53 and Golgi enzyme recycling assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via sequential siRNA depletions plus dominant-negative functional assays, single lab","pmids":["17699596"],"is_preprint":false},{"year":2007,"finding":"RINT-1 is localized at the Golgi apparatus, centrosome, and ER. Homozygous deletion of Rint1 causes early embryonic lethality (E5–E6). Heterozygous Rint1 mice develop multiple tumors, indicating haploinsufficiency-based tumor suppression. siRNA depletion of RINT-1 causes dispersal of Golgi (loss of pericentriolar positioning), centrosome amplification, aberrant Golgi dynamics during mitosis, multiple spindle poles, chromosome missegregation, and cell death.","method":"Immunofluorescence/subcellular fractionation for localization, mouse knockout (homozygous and heterozygous), siRNA knockdown with centrosome and Golgi phenotype readouts, time-lapse imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse KO with embryonic lethality, heterozygote tumor phenotype, siRNA with multiple orthogonal cellular phenotype readouts; multiple methods across in vivo and in vitro","pmids":["17470549"],"is_preprint":false},{"year":2013,"finding":"RINT-1 (mammalian ortholog of yeast Tip20/Dsl1 complex subunit) has a dual role: (1) in the ZW10 complex it mediates ER-localized SNARE interactions for Golgi-to-ER retrograde transport; (2) RINT-1 uncomplexed with ZW10 interacts with the COG complex and regulates SNARE complex assembly at the trans-Golgi network for endosome-to-TGN trafficking.","method":"Co-immunoprecipitation, siRNA knockdown, SNARE complex assembly assays, vesicle trafficking assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP defining two distinct complexes plus functional trafficking assays with siRNA, multiple orthogonal methods","pmids":["23885118"],"is_preprint":false},{"year":2015,"finding":"Conditional inactivation of Rint1 in neural progenitor cells in vivo causes genomic instability (chromosome fusions), ER stress, disruption of ER and cis/trans-Golgi homeostasis, and inhibition of autophagosome clearance (autophagic flux), leading to neurodegeneration and death at birth.","method":"Conditional knockout mouse (Cre-lox in neuroprogenitors), cytogenetics (chromosome fusion analysis), ER stress markers, immunofluorescence for Golgi/ER morphology, autophagy flux assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo with multiple orthogonal readouts (genomic instability, ER stress, Golgi morphology, autophagy) across multiple cell types","pmids":["26383973"],"is_preprint":false},{"year":2016,"finding":"RINT-1 interacts with MSP58 nucleolar protein; both proteins co-localize in the nucleolus with the rRNA transcription factor UBF. Overexpression of RINT-1 or MSP58 decreases rRNA expression and rDNA promoter activity, while siRNA knockdown of either has the opposite effect. Co-expression of both proteins robustly decreases rRNA synthesis. Both proteins associate with the rDNA promoter (ChIP assay), indicating a role for RINT-1 in repressing ribosomal gene transcription.","method":"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, immunofluorescence co-localization, reporter assay (rDNA promoter-luciferase), siRNA knockdown, chromatin immunoprecipitation (ChIP)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, co-localization, reporter, ChIP, siRNA) in single lab","pmids":["27530925"],"is_preprint":false},{"year":2019,"finding":"RINT1 interacts with NBAS and UVRAG to facilitate Golgi-to-ER retrograde vesicle transport. Bi-allelic loss-of-function RINT1 variants in patients caused decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux in dermal fibroblasts, establishing that RINT1 is required for Golgi-ER trafficking and autophagy in vivo.","method":"Patient-derived fibroblast analysis, co-immunoprecipitation (RINT1–NBAS–UVRAG), Golgi morphology imaging, autophagic flux assay (LC3-II), splice-variant characterization with NMD","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional cellular assays in patient fibroblasts, single lab, multiple orthogonal methods","pmids":["31204009"],"is_preprint":false},{"year":2020,"finding":"Conditional inactivation of Rint1 in retinal progenitor cells causes accumulation of endogenous DNA damage and TRP53-mediated apoptosis in proliferating progenitors and postmitotic neurons, leading to retinal ganglion cell neurogenesis defects and blindness. Inactivation of Trp53 rescued apoptosis and restored neurogenesis and vision, placing TRP53 downstream of RINT1 loss in apoptotic signaling.","method":"Conditional knockout mouse (retina-specific Cre-lox), double knockout (Rint1/Trp53), DNA damage markers (γH2AX), TUNEL apoptosis assay, cell cycle checkpoint analysis, histology, vision testing","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with genetic epistasis (Trp53 rescue), multiple phenotypic readouts, rigorous controls","pmids":["32850831"],"is_preprint":false},{"year":2021,"finding":"RINT1 loss in pancreatic cancer cells causes accumulation of DNA double-strand breaks, G2 arrest, disruption of Golgi-ER homeostasis, and defective SUMOylation. Quantitative proteome and interactome analyses after RINT1 depletion pointed to impaired nucleocytoplasmic transport and DSB response as downstream consequences of defective SUMOylation.","method":"shRNA/siRNA knockdown, time-resolved transcriptomics, quantitative proteomics, interactome (MS), in vivo xenograft models, organoid culture, DNA damage markers","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal omics methods plus in vivo validation; SUMOylation link is primarily proteomics-inferred rather than direct biochemical reconstitution","pmids":["33531371"],"is_preprint":false},{"year":2023,"finding":"Pathogenic RINT1 loss-of-function variants cause defective lipid-droplet biogenesis and lipid abnormalities (decreased triglycerides, diglycerides, phosphatidylcholine/phosphatidylserine ratios, inhibited Lands cycle) in fibroblasts and plasma. RINT1 mutations also induce intracellular ROS production, reduced ATP synthesis, mitochondrial membrane depolarization, aberrant cristae ultrastructure, and increased mitochondrial fission, establishing RINT1 as a regulator of lipid metabolism and mitochondrial function.","method":"Patient fibroblasts from biallelic RINT1 variants, lipidomics, ROS assays, mitochondrial membrane potential assays, electron microscopy (cristae ultrastructure), ATP synthesis measurement, mitochondrial morphology analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in patient-derived cells, single lab, no reconstitution","pmids":["37463447"],"is_preprint":false},{"year":2025,"finding":"Missense variants in RINT1 (p.His221Pro and p.Ala368Thr) disrupt ER tether and SNARE interactions as shown by immunoprecipitation of recombinant mutant proteins. These variants also impair autophagic flux (LC3-II turnover assay). Fat-body-specific Rint1 knockdown in Drosophila caused tissue atrophy and decreased lipid droplets, confirming a role in lipid storage.","method":"Immunoprecipitation of recombinant mutant proteins, LC3-II turnover assay, Drosophila fat-body-specific RNAi knockdown with lipid droplet and morphology analysis, qPCR for UPR genes","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP of mutants, autophagy flux, in vivo Drosophila model) in single study","pmids":["40940405"],"is_preprint":false},{"year":2026,"finding":"RNF39, an E3 ubiquitin ligase, directly interacts with RINT1, polyubiquitinates it via K48-linked chains, and promotes its proteasomal degradation. RNF39-mediated RINT1 degradation suppresses the UPR/CHOP-mediated ER stress apoptosis pathway in colorectal cancer cells; RINT1 knockdown partially rescues the anti-tumor effects of RNF39 loss.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linked polyubiquitination), proteasome inhibition, shRNA/CRISPR knockdown and overexpression, in vivo xenograft","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus rescue epistasis experiment, single lab","pmids":["41457280"],"is_preprint":false},{"year":2026,"finding":"BRIP1 acetylates RINT1 at lysine 728, which strengthens the RINT1–RAD50 interaction and facilitates assembly of the MRE11–RAD50–NBS1 (MRN) complex, thereby enhancing homologous recombination-mediated DNA repair. Enhanced repair limits cytosolic DNA accumulation and suppresses cGAS-STING-dependent innate immune activation in lung adenocarcinoma.","method":"Co-immunoprecipitation (BRIP1–RINT1 interaction), acetylation assay (K728), MRN complex assembly assay, HR repair assay, cGAS-STING pathway activation measurement, in vivo tumor models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus site-specific PTM identification (K728 acetylation) plus functional complex assembly assay, single lab","pmids":["41740833"],"is_preprint":false}],"current_model":"RINT1 is a multifunctional scaffold protein that operates at the ER membrane as a linker between the ZW10 tethering complex and the syntaxin 18 SNARE machinery to mediate Golgi-to-ER retrograde vesicle transport, and independently associates with the COG complex to support endosome-to-trans-Golgi network trafficking; it also interacts with Rad50 during late S/G2-M to support the radiation-induced G2/M checkpoint and homologous recombination (with its K728 acetylation by BRIP1 strengthening the MRN complex), controls telomere length via a p130–RINT1–Rad50 complex, maintains Golgi and centrosome integrity during cell division, supports autophagic flux, regulates lipid metabolism and mitochondrial function, and is subject to proteasomal degradation via K48-linked ubiquitination by RNF39."},"narrative":{"mechanistic_narrative":"RINT1 is a multifunctional ER-associated scaffold that coordinates membrane trafficking, genome stability, and organelle homeostasis [PMID:17470549, PMID:23885118]. At the ER membrane it acts as the obligate linker that recruits the ZW10 tethering factor into the syntaxin 18 (STX18) SNARE complex, enabling Golgi-to-ER retrograde vesicle transport; loss of RINT1 displaces ZW10 and blocks transport, and RINT1 occupies the SNARE complex independently of ZW10 [PMID:16571679, PMID:23885118]. A ZW10-uncoupled pool of RINT1 instead associates with the COG complex to drive SNARE assembly at the trans-Golgi network for endosome-to-TGN trafficking, and the protein further partners with NBAS and UVRAG to sustain retrograde transport and autophagic flux [PMID:23885118, PMID:31204009]. Through these trafficking roles RINT1 maintains pericentriolar Golgi positioning, centrosome integrity, and proper mitotic Golgi dynamics, such that its depletion produces centrosome amplification, multipolar spindles, and chromosome missegregation [PMID:17470549]. Independently, RINT1 binds the C-terminus of Rad50 specifically in late S/G2-M to support the radiation-induced G2/M checkpoint, and a p130–RINT1–Rad50 complex restrains recombination-based telomere lengthening [PMID:11096100, PMID:16600870]; its acetylation at K728 by BRIP1 strengthens the Rad50 interaction and promotes MRN complex assembly for homologous-recombination repair [PMID:41740833]. RINT1 is haploinsufficient for tumor suppression and essential for viability, with homozygous knockout causing embryonic lethality, and biallelic loss-of-function variants in patients impair Golgi-ER trafficking, autophagy, lipid-droplet biogenesis, and mitochondrial function [PMID:17470549, PMID:31204009, PMID:37463447]. RINT1 levels are set by RNF39, which catalyzes K48-linked polyubiquitination and proteasomal degradation, modulating UPR/CHOP-mediated ER-stress apoptosis [PMID:41457280].","teleology":[{"year":2000,"claim":"Established the first molecular partner and a cell-cycle-restricted function for RINT1, linking it to the DNA-damage checkpoint machinery.","evidence":"Yeast two-hybrid with Rad50 C-terminal bait, co-IP, and truncation-mutant expression in MCF-7 cells","pmids":["11096100"],"confidence":"Medium","gaps":["Did not define the direct biochemical role of RINT1 in checkpoint signaling","No structural basis for the Rad50 interaction","Phase-specific binding mechanism unexplained"]},{"year":2006,"claim":"Resolved how RINT1 acts in ER membrane trafficking by showing it is the linker bridging ZW10 to the syntaxin 18 SNARE complex.","evidence":"Reciprocal siRNA knockdown epistasis, co-IP, transport assays, and Golgi imaging","pmids":["16571679"],"confidence":"High","gaps":["Did not reconstitute the SNARE complex in vitro","Stoichiometry of the RINT1-ZW10-STX18 assembly unresolved"]},{"year":2006,"claim":"Extended RINT1's Rad50 partnership into telomere maintenance via a p130-RINT1-Rad50 complex restraining recombination-based lengthening.","evidence":"Co-IP, loss-of-function, and telomere length assays","pmids":["16600870"],"confidence":"Medium","gaps":["Mechanism by which the complex blocks recombination undefined","No direct demonstration of complex assembly on telomeric DNA"]},{"year":2007,"claim":"Demonstrated RINT1 is essential and a haploinsufficient tumor suppressor that maintains Golgi/centrosome integrity and mitotic fidelity.","evidence":"Mouse knockout (embryonic lethality, heterozygote tumors), siRNA with centrosome/Golgi/spindle readouts, time-lapse imaging, and localization studies; plus siRNA epistasis placing RINT1/ZW10 upstream of Rab6-dynein","pmids":["17470549","17699596"],"confidence":"High","gaps":["Did not separate trafficking from genome-stability contributions to tumor suppression","Direct molecular link between Golgi dispersal and centrosome amplification unclear"]},{"year":2013,"claim":"Defined a dual, ZW10-dependent and ZW10-independent role, with a COG-associated pool acting at the TGN.","evidence":"Co-IP defining two complexes, siRNA, SNARE assembly and vesicle trafficking assays","pmids":["23885118"],"confidence":"High","gaps":["What partitions RINT1 between ZW10 and COG pools is unknown","No structural model of either complex"]},{"year":2015,"claim":"Linked RINT1 loss in vivo to combined genomic instability, ER stress, Golgi disruption, and blocked autophagic flux causing neurodegeneration.","evidence":"Neuroprogenitor conditional knockout with cytogenetics, ER-stress markers, Golgi imaging, and autophagy flux assays","pmids":["26383973"],"confidence":"High","gaps":["Causal ordering among the four defects not established","Mechanism connecting trafficking loss to chromosome fusions unresolved"]},{"year":2016,"claim":"Identified an unexpected nucleolar function for RINT1 as a repressor of ribosomal gene transcription via MSP58.","evidence":"Yeast two-hybrid, pull-down, co-IP, co-localization with UBF, rDNA reporter, ChIP, and siRNA","pmids":["27530925"],"confidence":"Medium","gaps":["How an ER/trafficking scaffold reaches the nucleolus unexplained","Direct effect on Pol I machinery not shown","Single-lab finding"]},{"year":2019,"claim":"Established RINT1 as a human disease gene, with biallelic loss-of-function impairing Golgi-ER trafficking and autophagy via NBAS and UVRAG.","evidence":"Patient fibroblast analysis, RINT1-NBAS-UVRAG co-IP, Golgi imaging, LC3-II autophagy flux, splice-variant/NMD characterization","pmids":["31204009"],"confidence":"Medium","gaps":["Direct architecture of the RINT1-NBAS-UVRAG complex undefined","Single-cohort patient material"]},{"year":2020,"claim":"Placed TRP53 downstream of RINT1 loss in apoptotic signaling driving neurodegeneration.","evidence":"Retina-specific conditional knockout, Rint1/Trp53 double knockout rescue, γH2AX, TUNEL, and vision testing","pmids":["32850831"],"confidence":"High","gaps":["Source of endogenous DNA damage upon RINT1 loss not pinned down","Does not address non-apoptotic RINT1 functions"]},{"year":2021,"claim":"Connected RINT1 loss in cancer cells to defective SUMOylation, impaired nucleocytoplasmic transport, and DSB accumulation.","evidence":"shRNA/siRNA knockdown, transcriptomics, quantitative proteomics, interactome MS, xenografts, and organoids","pmids":["33531371"],"confidence":"Medium","gaps":["SUMOylation link is proteomics-inferred, not biochemically reconstituted","Direct substrate relationships unverified"]},{"year":2023,"claim":"Revealed metabolic roles of RINT1 in lipid-droplet biogenesis, lipid homeostasis, and mitochondrial integrity.","evidence":"Patient fibroblast lipidomics, ROS and mitochondrial membrane potential assays, electron microscopy, and ATP measurements","pmids":["37463447"],"confidence":"Medium","gaps":["Whether mitochondrial defects are direct or secondary to trafficking/ER stress unclear","No reconstitution of a lipid-handling activity"]},{"year":2025,"claim":"Showed specific missense variants disrupt ER tether/SNARE interactions and autophagy, and confirmed a conserved lipid-storage role in vivo.","evidence":"IP of recombinant mutant proteins, LC3-II turnover, Drosophila fat-body RNAi with lipid-droplet analysis, and UPR qPCR","pmids":["40940405"],"confidence":"Medium","gaps":["Structural basis for variant-induced interaction loss not solved","Genotype-phenotype correlation across variants limited"]},{"year":2026,"claim":"Defined post-translational control of RINT1 abundance by RNF39-mediated K48 ubiquitination governing ER-stress apoptosis.","evidence":"Co-IP, K48-linked ubiquitination assay, proteasome inhibition, knockdown/overexpression rescue, and xenografts","pmids":["41457280"],"confidence":"Medium","gaps":["Ubiquitination site(s) on RINT1 not mapped","Signals controlling RNF39 activity unknown"]},{"year":2026,"claim":"Identified an activating acetylation (K728 by BRIP1) that promotes MRN assembly and HR repair, dampening cGAS-STING innate immunity.","evidence":"Co-IP, site-specific acetylation assay, MRN assembly and HR repair assays, cGAS-STING readouts, and tumor models","pmids":["41740833"],"confidence":"Medium","gaps":["Structural effect of K728 acetylation on the RINT1-Rad50 interface unresolved","Deacetylase counterpart not identified"]},{"year":null,"claim":"How RINT1 is partitioned among its ER trafficking, nucleolar, genome-stability, and metabolic roles, and how these are coordinated within a cell, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of RINT1 in any of its complexes","Mechanism coupling membrane-trafficking defects to genomic instability undefined","Regulatory logic governing pool selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,13]}],"complexes":["syntaxin 18 (STX18) SNARE complex","ZW10 tethering complex","COG complex","p130-RINT1-Rad50 complex"],"partners":["RAD50","ZW10","STX18","P130","NBAS","UVRAG","RNF39","BRIP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NUQ1","full_name":"RAD50-interacting protein 1","aliases":["RAD50 interactor 1","HsRINT-1","RINT-1"],"length_aa":792,"mass_kda":90.6,"function":"Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER. May play a role in cell cycle checkpoint control (PubMed:11096100). Essential for telomere length control (PubMed:16600870)","subcellular_location":"Cytoplasm; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6NUQ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RINT1","classification":"Common Essential","n_dependent_lines":1072,"n_total_lines":1208,"dependency_fraction":0.8874172185430463},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BNIP1","stoichiometry":4.0},{"gene":"STX18","stoichiometry":4.0},{"gene":"GOLT1B","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"SCFD1","stoichiometry":0.2},{"gene":"STX3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RINT1","total_profiled":1310},"omim":[{"mim_id":"618641","title":"INFANTILE LIVER FAILURE SYNDROME 3; ILFS3","url":"https://www.omim.org/entry/618641"},{"mim_id":"615438","title":"INFANTILE LIVER FAILURE SYNDROME 1; ILFS1","url":"https://www.omim.org/entry/615438"},{"mim_id":"610089","title":"RAD50-INTERACTING PROTEIN 1; RINT1","url":"https://www.omim.org/entry/610089"},{"mim_id":"608025","title":"NBAS SUBUNIT OF NRZ TETHERING COMPLEX; NBAS","url":"https://www.omim.org/entry/608025"},{"mim_id":"180203","title":"RB TRANSCRIPTIONAL COREPRESSOR-LIKE 2; RBL2","url":"https://www.omim.org/entry/180203"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RINT1"},"hgnc":{"alias_symbol":["FLJ11785","RINT-1"],"prev_symbol":[]},"alphafold":{"accession":"Q6NUQ1","domains":[{"cath_id":"-","chopping":"287-431","consensus_level":"medium","plddt":93.1652,"start":287,"end":431},{"cath_id":"1.10.357,1.20.1310","chopping":"436-603","consensus_level":"high","plddt":89.2349,"start":436,"end":603},{"cath_id":"1.20.58","chopping":"626-784","consensus_level":"high","plddt":90.7839,"start":626,"end":784}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NUQ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NUQ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NUQ1-F1-predicted_aligned_error_v6.png","plddt_mean":85.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RINT1","jax_strain_url":"https://www.jax.org/strain/search?query=RINT1"},"sequence":{"accession":"Q6NUQ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NUQ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NUQ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NUQ1"}},"corpus_meta":[{"pmid":"17699596","id":"PMC_17699596","title":"Rab6 regulates both ZW10/RINT-1 and conserved oligomeric Golgi complex-dependent Golgi trafficking and homeostasis.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17699596","citation_count":79,"is_preprint":false},{"pmid":"16571679","id":"PMC_16571679","title":"RINT-1 regulates the localization and entry of ZW10 to the syntaxin 18 complex.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16571679","citation_count":68,"is_preprint":false},{"pmid":"11096100","id":"PMC_11096100","title":"RINT-1, a novel Rad50-interacting protein, participates in radiation-induced G(2)/M checkpoint control.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11096100","citation_count":56,"is_preprint":false},{"pmid":"31204009","id":"PMC_31204009","title":"RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31204009","citation_count":46,"is_preprint":false},{"pmid":"17470549","id":"PMC_17470549","title":"RINT-1 serves as a tumor suppressor and maintains Golgi dynamics and centrosome integrity for cell survival.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17470549","citation_count":41,"is_preprint":false},{"pmid":"16600870","id":"PMC_16600870","title":"The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16600870","citation_count":40,"is_preprint":false},{"pmid":"25050558","id":"PMC_25050558","title":"Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers.","date":"2014","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/25050558","citation_count":39,"is_preprint":false},{"pmid":"26383973","id":"PMC_26383973","title":"Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain.","date":"2015","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/26383973","citation_count":23,"is_preprint":false},{"pmid":"23885118","id":"PMC_23885118","title":"A new role for RINT-1 in SNARE complex assembly at the trans-Golgi network in coordination with the COG complex.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23885118","citation_count":21,"is_preprint":false},{"pmid":"38279772","id":"PMC_38279772","title":"Disorders of vesicular trafficking presenting with recurrent acute liver failure: NBAS, RINT1, and SCYL1 deficiency.","date":"2024","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/38279772","citation_count":20,"is_preprint":false},{"pmid":"27544226","id":"PMC_27544226","title":"Reevaluation of RINT1 as a breast cancer predisposition gene.","date":"2016","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/27544226","citation_count":19,"is_preprint":false},{"pmid":"23074196","id":"PMC_23074196","title":"Integrative functional genomics identifies RINT1 as a novel GBM oncogene.","date":"2012","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23074196","citation_count":16,"is_preprint":false},{"pmid":"37463447","id":"PMC_37463447","title":"RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37463447","citation_count":14,"is_preprint":false},{"pmid":"33531371","id":"PMC_33531371","title":"RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33531371","citation_count":12,"is_preprint":false},{"pmid":"25304616","id":"PMC_25304616","title":"Expression of RINT1 predicts seizure occurrence and outcomes in patients with low-grade gliomas.","date":"2014","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25304616","citation_count":12,"is_preprint":false},{"pmid":"27367497","id":"PMC_27367497","title":"RINT1 functions as a multitasking protein at the crossroads between genomic stability, ER homeostasis, and autophagy.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27367497","citation_count":10,"is_preprint":false},{"pmid":"28264000","id":"PMC_28264000","title":"Evaluation of Rint1 as a modifier of intestinal tumorigenesis and cancer risk.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28264000","citation_count":6,"is_preprint":false},{"pmid":"32850831","id":"PMC_32850831","title":"RINT1 Loss Impairs Retinogenesis Through TRP53-Mediated Apoptosis.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32850831","citation_count":5,"is_preprint":false},{"pmid":"27530925","id":"PMC_27530925","title":"RINT-1 interacts with MSP58 within nucleoli and plays a role in ribosomal gene transcription.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27530925","citation_count":4,"is_preprint":false},{"pmid":"41457280","id":"PMC_41457280","title":"RNF39 promotes colorectal cancer progression by driving RINT1 degradation and suppressing ER stress-induced apoptosis.","date":"2026","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41457280","citation_count":1,"is_preprint":false},{"pmid":"40940405","id":"PMC_40940405","title":"Functional analysis of novel and recurrent RINT1 variants in patients with infantile liver dysfunction.","date":"2025","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40940405","citation_count":1,"is_preprint":false},{"pmid":"41740833","id":"PMC_41740833","title":"BRIP1-mediated RINT1 acetylation and NF-κB activation promote DNA repair and immunosuppressive microenvironment in lung adenocarcinoma.","date":"2026","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/41740833","citation_count":0,"is_preprint":false},{"pmid":"32956753","id":"PMC_32956753","title":"The N-terminus region of Drp1, a Rint1 family protein is essential for cell survival and its interaction with Rad50 protein in fission yeast S.pombe.","date":"2020","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/32956753","citation_count":0,"is_preprint":false},{"pmid":"41158795","id":"PMC_41158795","title":"Recurrent fever-associated acute liver failure and cranial dysmorphism in children caused by RINT1 gene mutations: a rare case report.","date":"2025","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/41158795","citation_count":0,"is_preprint":false},{"pmid":"41057908","id":"PMC_41057908","title":"Recurrent acute liver failure and neutropenia caused by a novel homozygous RINT1 variant: a brief report of phenotypic expansion and population-specific findings.","date":"2025","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41057908","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14877,"output_tokens":4459,"usd":0.055758,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12412,"output_tokens":4505,"usd":0.087343,"stage2_stop_reason":"end_turn"},"total_usd":0.143101,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"RINT-1 was identified as a novel Rad50-interacting protein via yeast two-hybrid screen using the C-terminal region of human Rad50 as bait. The conserved central and C-terminal regions of RINT-1 are required for interaction with Rad50. RINT-1 specifically binds Rad50 only during late S and G2/M phases. Expression of N-terminally truncated RINT-1 in MCF-7 cells produced a defective radiation-induced G2/M checkpoint.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, cell cycle phase analysis, truncation mutant expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus truncation mutant functional assay in a single lab, two orthogonal methods\",\n      \"pmids\": [\"11096100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RINT-1 regulates the localization and entry of ZW10 into the syntaxin 18 (STX18) SNARE complex at the ER. The N-terminal region of RINT-1 mediates interaction with ZW10. Overexpression of RINT-1 N-terminus caused ZW10 redistribution and blocked ER-to-Golgi transport. Knockdown of RINT-1 reduced ZW10 association with syntaxin 18 and redistributed ZW10, while knockdown of ZW10 did not displace RINT-1 from the syntaxin 18 complex, establishing RINT-1 as the linker between ZW10 and the STX18 SNARE complex.\",\n      \"method\": \"siRNA knockdown, overexpression of truncation mutants, co-immunoprecipitation, Golgi morphology imaging, ER-to-Golgi transport assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdown epistasis, co-IP, transport assay, and localization imaging with functional consequence, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16571679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"p130 (Rb-related protein) interacts specifically with RINT-1, and both p130 and RINT-1 are essential for telomere length control. A complex of p130–RINT-1–Rad50 was proposed to block telomerase-independent (recombination-based) telomere lengthening in normal cells.\",\n      \"method\": \"Co-immunoprecipitation, genetic loss-of-function (siRNA/dominant-negative), telomere length assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional telomere assay in single lab, two orthogonal methods\",\n      \"pmids\": [\"16600870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RINT-1 functions downstream of or in a parallel pathway to Rab6 for Golgi homeostasis: epistatic siRNA depletion showed that Rab6 depletion inhibited Golgi disruption caused by RINT-1 (or ZW10) knockdown. Dominant-negative GDP-Rab6 suppressed ZW10-knockdown-induced Golgi disruption. A C-terminal fragment of Bicaudal D (linker between Rab6 and dynactin/dynein) suppressed ZW10 but not COG knockdown-induced Golgi disruption, placing RINT-1/ZW10 upstream of Rab6-dynein axis.\",\n      \"method\": \"siRNA epistasis, dominant-negative expression, Golgi morphology imaging, ERGIC53 and Golgi enzyme recycling assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via sequential siRNA depletions plus dominant-negative functional assays, single lab\",\n      \"pmids\": [\"17699596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RINT-1 is localized at the Golgi apparatus, centrosome, and ER. Homozygous deletion of Rint1 causes early embryonic lethality (E5–E6). Heterozygous Rint1 mice develop multiple tumors, indicating haploinsufficiency-based tumor suppression. siRNA depletion of RINT-1 causes dispersal of Golgi (loss of pericentriolar positioning), centrosome amplification, aberrant Golgi dynamics during mitosis, multiple spindle poles, chromosome missegregation, and cell death.\",\n      \"method\": \"Immunofluorescence/subcellular fractionation for localization, mouse knockout (homozygous and heterozygous), siRNA knockdown with centrosome and Golgi phenotype readouts, time-lapse imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse KO with embryonic lethality, heterozygote tumor phenotype, siRNA with multiple orthogonal cellular phenotype readouts; multiple methods across in vivo and in vitro\",\n      \"pmids\": [\"17470549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RINT-1 (mammalian ortholog of yeast Tip20/Dsl1 complex subunit) has a dual role: (1) in the ZW10 complex it mediates ER-localized SNARE interactions for Golgi-to-ER retrograde transport; (2) RINT-1 uncomplexed with ZW10 interacts with the COG complex and regulates SNARE complex assembly at the trans-Golgi network for endosome-to-TGN trafficking.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, SNARE complex assembly assays, vesicle trafficking assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP defining two distinct complexes plus functional trafficking assays with siRNA, multiple orthogonal methods\",\n      \"pmids\": [\"23885118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Conditional inactivation of Rint1 in neural progenitor cells in vivo causes genomic instability (chromosome fusions), ER stress, disruption of ER and cis/trans-Golgi homeostasis, and inhibition of autophagosome clearance (autophagic flux), leading to neurodegeneration and death at birth.\",\n      \"method\": \"Conditional knockout mouse (Cre-lox in neuroprogenitors), cytogenetics (chromosome fusion analysis), ER stress markers, immunofluorescence for Golgi/ER morphology, autophagy flux assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo with multiple orthogonal readouts (genomic instability, ER stress, Golgi morphology, autophagy) across multiple cell types\",\n      \"pmids\": [\"26383973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RINT-1 interacts with MSP58 nucleolar protein; both proteins co-localize in the nucleolus with the rRNA transcription factor UBF. Overexpression of RINT-1 or MSP58 decreases rRNA expression and rDNA promoter activity, while siRNA knockdown of either has the opposite effect. Co-expression of both proteins robustly decreases rRNA synthesis. Both proteins associate with the rDNA promoter (ChIP assay), indicating a role for RINT-1 in repressing ribosomal gene transcription.\",\n      \"method\": \"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, immunofluorescence co-localization, reporter assay (rDNA promoter-luciferase), siRNA knockdown, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, co-localization, reporter, ChIP, siRNA) in single lab\",\n      \"pmids\": [\"27530925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RINT1 interacts with NBAS and UVRAG to facilitate Golgi-to-ER retrograde vesicle transport. Bi-allelic loss-of-function RINT1 variants in patients caused decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux in dermal fibroblasts, establishing that RINT1 is required for Golgi-ER trafficking and autophagy in vivo.\",\n      \"method\": \"Patient-derived fibroblast analysis, co-immunoprecipitation (RINT1–NBAS–UVRAG), Golgi morphology imaging, autophagic flux assay (LC3-II), splice-variant characterization with NMD\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional cellular assays in patient fibroblasts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31204009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional inactivation of Rint1 in retinal progenitor cells causes accumulation of endogenous DNA damage and TRP53-mediated apoptosis in proliferating progenitors and postmitotic neurons, leading to retinal ganglion cell neurogenesis defects and blindness. Inactivation of Trp53 rescued apoptosis and restored neurogenesis and vision, placing TRP53 downstream of RINT1 loss in apoptotic signaling.\",\n      \"method\": \"Conditional knockout mouse (retina-specific Cre-lox), double knockout (Rint1/Trp53), DNA damage markers (γH2AX), TUNEL apoptosis assay, cell cycle checkpoint analysis, histology, vision testing\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with genetic epistasis (Trp53 rescue), multiple phenotypic readouts, rigorous controls\",\n      \"pmids\": [\"32850831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RINT1 loss in pancreatic cancer cells causes accumulation of DNA double-strand breaks, G2 arrest, disruption of Golgi-ER homeostasis, and defective SUMOylation. Quantitative proteome and interactome analyses after RINT1 depletion pointed to impaired nucleocytoplasmic transport and DSB response as downstream consequences of defective SUMOylation.\",\n      \"method\": \"shRNA/siRNA knockdown, time-resolved transcriptomics, quantitative proteomics, interactome (MS), in vivo xenograft models, organoid culture, DNA damage markers\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal omics methods plus in vivo validation; SUMOylation link is primarily proteomics-inferred rather than direct biochemical reconstitution\",\n      \"pmids\": [\"33531371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pathogenic RINT1 loss-of-function variants cause defective lipid-droplet biogenesis and lipid abnormalities (decreased triglycerides, diglycerides, phosphatidylcholine/phosphatidylserine ratios, inhibited Lands cycle) in fibroblasts and plasma. RINT1 mutations also induce intracellular ROS production, reduced ATP synthesis, mitochondrial membrane depolarization, aberrant cristae ultrastructure, and increased mitochondrial fission, establishing RINT1 as a regulator of lipid metabolism and mitochondrial function.\",\n      \"method\": \"Patient fibroblasts from biallelic RINT1 variants, lipidomics, ROS assays, mitochondrial membrane potential assays, electron microscopy (cristae ultrastructure), ATP synthesis measurement, mitochondrial morphology analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in patient-derived cells, single lab, no reconstitution\",\n      \"pmids\": [\"37463447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Missense variants in RINT1 (p.His221Pro and p.Ala368Thr) disrupt ER tether and SNARE interactions as shown by immunoprecipitation of recombinant mutant proteins. These variants also impair autophagic flux (LC3-II turnover assay). Fat-body-specific Rint1 knockdown in Drosophila caused tissue atrophy and decreased lipid droplets, confirming a role in lipid storage.\",\n      \"method\": \"Immunoprecipitation of recombinant mutant proteins, LC3-II turnover assay, Drosophila fat-body-specific RNAi knockdown with lipid droplet and morphology analysis, qPCR for UPR genes\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP of mutants, autophagy flux, in vivo Drosophila model) in single study\",\n      \"pmids\": [\"40940405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF39, an E3 ubiquitin ligase, directly interacts with RINT1, polyubiquitinates it via K48-linked chains, and promotes its proteasomal degradation. RNF39-mediated RINT1 degradation suppresses the UPR/CHOP-mediated ER stress apoptosis pathway in colorectal cancer cells; RINT1 knockdown partially rescues the anti-tumor effects of RNF39 loss.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linked polyubiquitination), proteasome inhibition, shRNA/CRISPR knockdown and overexpression, in vivo xenograft\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus rescue epistasis experiment, single lab\",\n      \"pmids\": [\"41457280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"BRIP1 acetylates RINT1 at lysine 728, which strengthens the RINT1–RAD50 interaction and facilitates assembly of the MRE11–RAD50–NBS1 (MRN) complex, thereby enhancing homologous recombination-mediated DNA repair. Enhanced repair limits cytosolic DNA accumulation and suppresses cGAS-STING-dependent innate immune activation in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation (BRIP1–RINT1 interaction), acetylation assay (K728), MRN complex assembly assay, HR repair assay, cGAS-STING pathway activation measurement, in vivo tumor models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus site-specific PTM identification (K728 acetylation) plus functional complex assembly assay, single lab\",\n      \"pmids\": [\"41740833\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RINT1 is a multifunctional scaffold protein that operates at the ER membrane as a linker between the ZW10 tethering complex and the syntaxin 18 SNARE machinery to mediate Golgi-to-ER retrograde vesicle transport, and independently associates with the COG complex to support endosome-to-trans-Golgi network trafficking; it also interacts with Rad50 during late S/G2-M to support the radiation-induced G2/M checkpoint and homologous recombination (with its K728 acetylation by BRIP1 strengthening the MRN complex), controls telomere length via a p130–RINT1–Rad50 complex, maintains Golgi and centrosome integrity during cell division, supports autophagic flux, regulates lipid metabolism and mitochondrial function, and is subject to proteasomal degradation via K48-linked ubiquitination by RNF39.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RINT1 is a multifunctional ER-associated scaffold that coordinates membrane trafficking, genome stability, and organelle homeostasis [#4, #5]. At the ER membrane it acts as the obligate linker that recruits the ZW10 tethering factor into the syntaxin 18 (STX18) SNARE complex, enabling Golgi-to-ER retrograde vesicle transport; loss of RINT1 displaces ZW10 and blocks transport, and RINT1 occupies the SNARE complex independently of ZW10 [#1, #5]. A ZW10-uncoupled pool of RINT1 instead associates with the COG complex to drive SNARE assembly at the trans-Golgi network for endosome-to-TGN trafficking, and the protein further partners with NBAS and UVRAG to sustain retrograde transport and autophagic flux [#5, #8]. Through these trafficking roles RINT1 maintains pericentriolar Golgi positioning, centrosome integrity, and proper mitotic Golgi dynamics, such that its depletion produces centrosome amplification, multipolar spindles, and chromosome missegregation [#4]. Independently, RINT1 binds the C-terminus of Rad50 specifically in late S/G2-M to support the radiation-induced G2/M checkpoint, and a p130\\u2013RINT1\\u2013Rad50 complex restrains recombination-based telomere lengthening [#0, #2]; its acetylation at K728 by BRIP1 strengthens the Rad50 interaction and promotes MRN complex assembly for homologous-recombination repair [#14]. RINT1 is haploinsufficient for tumor suppression and essential for viability, with homozygous knockout causing embryonic lethality, and biallelic loss-of-function variants in patients impair Golgi-ER trafficking, autophagy, lipid-droplet biogenesis, and mitochondrial function [#4, #8, #11]. RINT1 levels are set by RNF39, which catalyzes K48-linked polyubiquitination and proteasomal degradation, modulating UPR/CHOP-mediated ER-stress apoptosis [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the first molecular partner and a cell-cycle-restricted function for RINT1, linking it to the DNA-damage checkpoint machinery.\",\n      \"evidence\": \"Yeast two-hybrid with Rad50 C-terminal bait, co-IP, and truncation-mutant expression in MCF-7 cells\",\n      \"pmids\": [\"11096100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the direct biochemical role of RINT1 in checkpoint signaling\", \"No structural basis for the Rad50 interaction\", \"Phase-specific binding mechanism unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how RINT1 acts in ER membrane trafficking by showing it is the linker bridging ZW10 to the syntaxin 18 SNARE complex.\",\n      \"evidence\": \"Reciprocal siRNA knockdown epistasis, co-IP, transport assays, and Golgi imaging\",\n      \"pmids\": [\"16571679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconstitute the SNARE complex in vitro\", \"Stoichiometry of the RINT1-ZW10-STX18 assembly unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended RINT1's Rad50 partnership into telomere maintenance via a p130-RINT1-Rad50 complex restraining recombination-based lengthening.\",\n      \"evidence\": \"Co-IP, loss-of-function, and telomere length assays\",\n      \"pmids\": [\"16600870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the complex blocks recombination undefined\", \"No direct demonstration of complex assembly on telomeric DNA\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated RINT1 is essential and a haploinsufficient tumor suppressor that maintains Golgi/centrosome integrity and mitotic fidelity.\",\n      \"evidence\": \"Mouse knockout (embryonic lethality, heterozygote tumors), siRNA with centrosome/Golgi/spindle readouts, time-lapse imaging, and localization studies; plus siRNA epistasis placing RINT1/ZW10 upstream of Rab6-dynein\",\n      \"pmids\": [\"17470549\", \"17699596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate trafficking from genome-stability contributions to tumor suppression\", \"Direct molecular link between Golgi dispersal and centrosome amplification unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a dual, ZW10-dependent and ZW10-independent role, with a COG-associated pool acting at the TGN.\",\n      \"evidence\": \"Co-IP defining two complexes, siRNA, SNARE assembly and vesicle trafficking assays\",\n      \"pmids\": [\"23885118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What partitions RINT1 between ZW10 and COG pools is unknown\", \"No structural model of either complex\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked RINT1 loss in vivo to combined genomic instability, ER stress, Golgi disruption, and blocked autophagic flux causing neurodegeneration.\",\n      \"evidence\": \"Neuroprogenitor conditional knockout with cytogenetics, ER-stress markers, Golgi imaging, and autophagy flux assays\",\n      \"pmids\": [\"26383973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal ordering among the four defects not established\", \"Mechanism connecting trafficking loss to chromosome fusions unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified an unexpected nucleolar function for RINT1 as a repressor of ribosomal gene transcription via MSP58.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down, co-IP, co-localization with UBF, rDNA reporter, ChIP, and siRNA\",\n      \"pmids\": [\"27530925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How an ER/trafficking scaffold reaches the nucleolus unexplained\", \"Direct effect on Pol I machinery not shown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established RINT1 as a human disease gene, with biallelic loss-of-function impairing Golgi-ER trafficking and autophagy via NBAS and UVRAG.\",\n      \"evidence\": \"Patient fibroblast analysis, RINT1-NBAS-UVRAG co-IP, Golgi imaging, LC3-II autophagy flux, splice-variant/NMD characterization\",\n      \"pmids\": [\"31204009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct architecture of the RINT1-NBAS-UVRAG complex undefined\", \"Single-cohort patient material\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed TRP53 downstream of RINT1 loss in apoptotic signaling driving neurodegeneration.\",\n      \"evidence\": \"Retina-specific conditional knockout, Rint1/Trp53 double knockout rescue, \\u03b3H2AX, TUNEL, and vision testing\",\n      \"pmids\": [\"32850831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of endogenous DNA damage upon RINT1 loss not pinned down\", \"Does not address non-apoptotic RINT1 functions\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected RINT1 loss in cancer cells to defective SUMOylation, impaired nucleocytoplasmic transport, and DSB accumulation.\",\n      \"evidence\": \"shRNA/siRNA knockdown, transcriptomics, quantitative proteomics, interactome MS, xenografts, and organoids\",\n      \"pmids\": [\"33531371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMOylation link is proteomics-inferred, not biochemically reconstituted\", \"Direct substrate relationships unverified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed metabolic roles of RINT1 in lipid-droplet biogenesis, lipid homeostasis, and mitochondrial integrity.\",\n      \"evidence\": \"Patient fibroblast lipidomics, ROS and mitochondrial membrane potential assays, electron microscopy, and ATP measurements\",\n      \"pmids\": [\"37463447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mitochondrial defects are direct or secondary to trafficking/ER stress unclear\", \"No reconstitution of a lipid-handling activity\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed specific missense variants disrupt ER tether/SNARE interactions and autophagy, and confirmed a conserved lipid-storage role in vivo.\",\n      \"evidence\": \"IP of recombinant mutant proteins, LC3-II turnover, Drosophila fat-body RNAi with lipid-droplet analysis, and UPR qPCR\",\n      \"pmids\": [\"40940405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for variant-induced interaction loss not solved\", \"Genotype-phenotype correlation across variants limited\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined post-translational control of RINT1 abundance by RNF39-mediated K48 ubiquitination governing ER-stress apoptosis.\",\n      \"evidence\": \"Co-IP, K48-linked ubiquitination assay, proteasome inhibition, knockdown/overexpression rescue, and xenografts\",\n      \"pmids\": [\"41457280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site(s) on RINT1 not mapped\", \"Signals controlling RNF39 activity unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an activating acetylation (K728 by BRIP1) that promotes MRN assembly and HR repair, dampening cGAS-STING innate immunity.\",\n      \"evidence\": \"Co-IP, site-specific acetylation assay, MRN assembly and HR repair assays, cGAS-STING readouts, and tumor models\",\n      \"pmids\": [\"41740833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural effect of K728 acetylation on the RINT1-Rad50 interface unresolved\", \"Deacetylase counterpart not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RINT1 is partitioned among its ER trafficking, nucleolar, genome-stability, and metabolic roles, and how these are coordinated within a cell, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of RINT1 in any of its complexes\", \"Mechanism coupling membrane-trafficking defects to genomic instability undefined\", \"Regulatory logic governing pool selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 13]}\n    ],\n    \"complexes\": [\n      \"syntaxin 18 (STX18) SNARE complex\",\n      \"ZW10 tethering complex\",\n      \"COG complex\",\n      \"p130-RINT1-Rad50 complex\"\n    ],\n    \"partners\": [\n      \"RAD50\",\n      \"ZW10\",\n      \"STX18\",\n      \"p130\",\n      \"NBAS\",\n      \"UVRAG\",\n      \"RNF39\",\n      \"BRIP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}