Affinage

RINT1

RAD50-interacting protein 1 · UniProt Q6NUQ1

Length
792 aa
Mass
90.6 kDa
Annotated
2026-06-10
25 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 Medium

    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

    PMID:11096100

    Open questions at the time
    • Did not define the direct biochemical role of RINT1 in checkpoint signaling
    • No structural basis for the Rad50 interaction
    • Phase-specific binding mechanism unexplained
  2. 2006 High

    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

    PMID:16571679

    Open questions at the time
    • Did not reconstitute the SNARE complex in vitro
    • Stoichiometry of the RINT1-ZW10-STX18 assembly unresolved
  3. 2006 Medium

    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

    PMID:16600870

    Open questions at the time
    • Mechanism by which the complex blocks recombination undefined
    • No direct demonstration of complex assembly on telomeric DNA
  4. 2007 High

    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

    PMID:17470549 PMID:17699596

    Open questions at the time
    • Did not separate trafficking from genome-stability contributions to tumor suppression
    • Direct molecular link between Golgi dispersal and centrosome amplification unclear
  5. 2013 High

    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

    PMID:23885118

    Open questions at the time
    • What partitions RINT1 between ZW10 and COG pools is unknown
    • No structural model of either complex
  6. 2015 High

    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

    PMID:26383973

    Open questions at the time
    • Causal ordering among the four defects not established
    • Mechanism connecting trafficking loss to chromosome fusions unresolved
  7. 2016 Medium

    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

    PMID:27530925

    Open questions at the time
    • How an ER/trafficking scaffold reaches the nucleolus unexplained
    • Direct effect on Pol I machinery not shown
    • Single-lab finding
  8. 2019 Medium

    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

    PMID:31204009

    Open questions at the time
    • Direct architecture of the RINT1-NBAS-UVRAG complex undefined
    • Single-cohort patient material
  9. 2020 High

    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

    PMID:32850831

    Open questions at the time
    • Source of endogenous DNA damage upon RINT1 loss not pinned down
    • Does not address non-apoptotic RINT1 functions
  10. 2021 Medium

    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

    PMID:33531371

    Open questions at the time
    • SUMOylation link is proteomics-inferred, not biochemically reconstituted
    • Direct substrate relationships unverified
  11. 2023 Medium

    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

    PMID:37463447

    Open questions at the time
    • Whether mitochondrial defects are direct or secondary to trafficking/ER stress unclear
    • No reconstitution of a lipid-handling activity
  12. 2025 Medium

    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

    PMID:40940405

    Open questions at the time
    • Structural basis for variant-induced interaction loss not solved
    • Genotype-phenotype correlation across variants limited
  13. 2026 Medium

    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

    PMID:41457280

    Open questions at the time
    • Ubiquitination site(s) on RINT1 not mapped
    • Signals controlling RNF39 activity unknown
  14. 2026 Medium

    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

    PMID:41740833

    Open questions at the time
    • Structural effect of K728 acetylation on the RINT1-Rad50 interface unresolved
    • Deacetylase counterpart not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RINT1 is partitioned among its ER trafficking, nucleolar, genome-stability, and metabolic roles, and how these are coordinated within a cell, remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 2 GO:0005730 nucleolus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-73894 DNA Repair 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2
Partners
BRIP1NBASP130RAD50RNF39STX18UVRAGZW10
Complex memberships
COG complexZW10 tethering complexp130-RINT1-Rad50 complexsyntaxin 18 (STX18) SNARE complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Yeast two-hybrid screen, co-immunoprecipitation, cell cycle phase analysis, truncation mutant expression The Journal of biological chemistry Medium 11096100
2006 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. siRNA knockdown, overexpression of truncation mutants, co-immunoprecipitation, Golgi morphology imaging, ER-to-Golgi transport assay Molecular biology of the cell High 16571679
2006 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. Co-immunoprecipitation, genetic loss-of-function (siRNA/dominant-negative), telomere length assays Molecular cell Medium 16600870
2007 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. siRNA epistasis, dominant-negative expression, Golgi morphology imaging, ERGIC53 and Golgi enzyme recycling assays Molecular biology of the cell Medium 17699596
2007 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. Immunofluorescence/subcellular fractionation for localization, mouse knockout (homozygous and heterozygous), siRNA knockdown with centrosome and Golgi phenotype readouts, time-lapse imaging Molecular and cellular biology High 17470549
2013 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. Co-immunoprecipitation, siRNA knockdown, SNARE complex assembly assays, vesicle trafficking assays Molecular biology of the cell High 23885118
2015 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. Conditional knockout mouse (Cre-lox in neuroprogenitors), cytogenetics (chromosome fusion analysis), ER stress markers, immunofluorescence for Golgi/ER morphology, autophagy flux assays Cell death and differentiation High 26383973
2016 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. Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, immunofluorescence co-localization, reporter assay (rDNA promoter-luciferase), siRNA knockdown, chromatin immunoprecipitation (ChIP) Biochemical and biophysical research communications Medium 27530925
2019 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. Patient-derived fibroblast analysis, co-immunoprecipitation (RINT1–NBAS–UVRAG), Golgi morphology imaging, autophagic flux assay (LC3-II), splice-variant characterization with NMD American journal of human genetics Medium 31204009
2020 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. 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 Frontiers in cell and developmental biology High 32850831
2021 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. shRNA/siRNA knockdown, time-resolved transcriptomics, quantitative proteomics, interactome (MS), in vivo xenograft models, organoid culture, DNA damage markers Cancer research Medium 33531371
2023 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. Patient fibroblasts from biallelic RINT1 variants, lipidomics, ROS assays, mitochondrial membrane potential assays, electron microscopy (cristae ultrastructure), ATP synthesis measurement, mitochondrial morphology analysis The Journal of clinical investigation Medium 37463447
2025 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. 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 of human genetics Medium 40940405
2026 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. Co-immunoprecipitation, ubiquitination assay (K48-linked polyubiquitination), proteasome inhibition, shRNA/CRISPR knockdown and overexpression, in vivo xenograft Clinical and translational medicine Medium 41457280
2026 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. Co-immunoprecipitation (BRIP1–RINT1 interaction), acetylation assay (K728), MRN complex assembly assay, HR repair assay, cGAS-STING pathway activation measurement, in vivo tumor models Cancer letters Medium 41740833

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Rab6 regulates both ZW10/RINT-1 and conserved oligomeric Golgi complex-dependent Golgi trafficking and homeostasis. Molecular biology of the cell 79 17699596
2006 RINT-1 regulates the localization and entry of ZW10 to the syntaxin 18 complex. Molecular biology of the cell 68 16571679
2000 RINT-1, a novel Rad50-interacting protein, participates in radiation-induced G(2)/M checkpoint control. The Journal of biological chemistry 56 11096100
2019 RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities. American journal of human genetics 46 31204009
2007 RINT-1 serves as a tumor suppressor and maintains Golgi dynamics and centrosome integrity for cell survival. Molecular and cellular biology 41 17470549
2006 The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1. Molecular cell 40 16600870
2014 Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers. Cancer discovery 39 25050558
2015 Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain. Cell death and differentiation 23 26383973
2013 A new role for RINT-1 in SNARE complex assembly at the trans-Golgi network in coordination with the COG complex. Molecular biology of the cell 21 23885118
2024 Disorders of vesicular trafficking presenting with recurrent acute liver failure: NBAS, RINT1, and SCYL1 deficiency. Journal of inherited metabolic disease 20 38279772
2016 Reevaluation of RINT1 as a breast cancer predisposition gene. Breast cancer research and treatment 19 27544226
2012 Integrative functional genomics identifies RINT1 as a novel GBM oncogene. Neuro-oncology 16 23074196
2023 RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia. The Journal of clinical investigation 14 37463447
2021 RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer. Cancer research 12 33531371
2014 Expression of RINT1 predicts seizure occurrence and outcomes in patients with low-grade gliomas. Journal of cancer research and clinical oncology 12 25304616
2016 RINT1 functions as a multitasking protein at the crossroads between genomic stability, ER homeostasis, and autophagy. Autophagy 10 27367497
2017 Evaluation of Rint1 as a modifier of intestinal tumorigenesis and cancer risk. PloS one 6 28264000
2020 RINT1 Loss Impairs Retinogenesis Through TRP53-Mediated Apoptosis. Frontiers in cell and developmental biology 5 32850831
2016 RINT-1 interacts with MSP58 within nucleoli and plays a role in ribosomal gene transcription. Biochemical and biophysical research communications 4 27530925
2026 RNF39 promotes colorectal cancer progression by driving RINT1 degradation and suppressing ER stress-induced apoptosis. Clinical and translational medicine 1 41457280
2025 Functional analysis of novel and recurrent RINT1 variants in patients with infantile liver dysfunction. Journal of human genetics 1 40940405
2026 BRIP1-mediated RINT1 acetylation and NF-κB activation promote DNA repair and immunosuppressive microenvironment in lung adenocarcinoma. Cancer letters 0 41740833
2025 Recurrent acute liver failure and neutropenia caused by a novel homozygous RINT1 variant: a brief report of phenotypic expansion and population-specific findings. Human genomics 0 41057908
2025 Recurrent fever-associated acute liver failure and cranial dysmorphism in children caused by RINT1 gene mutations: a rare case report. Frontiers in pediatrics 0 41158795
2020 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. Biochimica et biophysica acta. General subjects 0 32956753

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