Affinage

RUBCN

Run domain Beclin-1-interacting and cysteine-rich domain-containing protein · UniProt Q92622

Length
972 aa
Mass
108.6 kDa
Annotated
2026-06-10
91 papers in source corpus 30 papers cited in narrative 30 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

RUBCN (Rubicon) is a Rab7-effector scaffold that functions as a master negative regulator of late-stage autophagy and endolysosomal maturation, integrating membrane trafficking with innate immune signaling and metabolic control (PMID:19270696, PMID:30783089). It associates specifically with the UVRAG-containing Beclin 1–hVps34 (Class III PI3K) complex and, through its RUN domain, binds and inhibits the hVps34 lipid kinase, an interaction required for its suppression of autophagosome maturation (PMID:19270696, PMID:21062745). In parallel its C-terminal RH domain—a four-zinc-cluster fold resolved in complex with Rab7-GTP at 2.8 Å—binds Rab7 and is essential for late-endosomal/lysosomal localization, with GTP-loaded Rab7 competing for binding to release UVRAG to the HOPS complex and drive endosome maturation (PMID:20974968, PMID:20943950, PMID:32632011, PMID:23728897). Beyond canonical autophagy inhibition, Rubicon governs the autophagic turnover of specific substrates: it protects the PPARγ coactivators NCOA1/SRC-1 and NCOA2/TIF2 in adipocytes and the transcription factor GATA4 in Sertoli cells from degradation, linking its levels to adipose metabolism, hepatic lipid handling, and spermatogenesis (PMID:32811819, PMID:35282767, PMID:34351902). Age-dependent upregulation of Rubicon suppresses autophagy, and its loss extends lifespan and ameliorates fibrotic and proteinopathic phenotypes (PMID:30783089). Rubicon also performs autophagy-independent immune and trafficking functions: it binds the NADPH oxidase subunit p22phox to drive phagosomal ROS production (PMID:22423966), acts as a phosphorylation-dependent feedback inhibitor of CARD9-BCL10-MALT1 PRR signaling (PMID:22423967), suppresses type I interferon responses by inhibiting IRF3 dimerization and NEMO ubiquitination (PMID:28468885, PMID:28392573), and recruits WIPI2d to endosomes to promote ESCRT-dependent exosome biogenesis (PMID:39174742). Its abundance and activity are tightly controlled by HUNK-mediated inhibitory phosphorylation (PMID:31752345), HECTD1- and TRIM21-mediated ubiquitination (at K534 and via K48 linkages) targeting it for degradation (PMID:36121967, PMID:41187080), FXR- and m6A/METTL3-YTHDF1-driven expression (PMID:32001325, PMID:34547464), and a TBK1-dependent phospho-switch on Rab7A (Ser72) that severs Rubicon binding to relieve autophagy inhibition during mitophagy (PMID:38728007).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2009 High

    Established that Rubicon is a distinct subunit of the Beclin 1–Vps34 complex and a negative regulator acting at the autophagosome maturation step, answering where in the autophagy pathway it functions.

    Evidence Co-IP/MS, GFP localization, and siRNA flux assays defining UVRAG-specific complex membership; in vitro Vps34 kinase inhibition with genetics in two simultaneous papers

    PMID:19270693 PMID:19270696

    Open questions at the time
    • Domain responsible for Vps34 inhibition not yet mapped
    • Mechanism of late-endosome localization undefined
  2. 2010 High

    Defined the molecular architecture of Rubicon's two regulatory arms: the RH domain binds Rab7 and the RUN domain binds and inhibits hVps34, and clarified how Rab7-GTP competition couples Rubicon to endosome maturation.

    Evidence Direct binding/pulldown assays, RH and RUN deletion mutagenesis, dominant-negative/constitutively active Rab7, and complementation in knockdown cells

    PMID:20943950 PMID:20974968 PMID:21062745

    Open questions at the time
    • Structural basis of RH–Rab7 recognition not resolved
    • Stoichiometry of simultaneous Rab7 and PI3K binding unclear
  3. 2012 High

    Demonstrated that Rubicon has autophagy-independent innate immune roles, positively driving NADPH oxidase ROS and negatively feeding back on CARD9-CBM PRR signaling, broadening its function beyond trafficking.

    Evidence Reciprocal Co-IP with p22phox and CARD9, phosphorylation-dependent partner exchange, ROS/cytokine/antimicrobial readouts with genetic separation of functions

    PMID:22423966 PMID:22423967

    Open questions at the time
    • Kinase mediating the 14-3-3β/CARD9 phospho-switch not identified
    • Domains mediating p22phox binding undefined
  4. 2013 Medium

    Linked the RH domain directly to subcellular targeting and human disease by showing a Salih ataxia frameshift mutation mislocalizes Rubicon to the cytosol.

    Evidence Fluorescence colocalization of mutant vs wild-type Rubicon with Rab7/LAMP1 in cultured cells

    PMID:23728897

    Open questions at the time
    • Single-lab localization inference without functional autophagy rescue
    • Causal link between mislocalization and ataxia phenotype not established in patients
  5. 2017 Medium

    Extended Rubicon's immune-suppressive role to antiviral signaling, showing it inhibits IRF3 dimerization and NEMO ubiquitination to dampen interferon production.

    Evidence Co-IP with IRF3 IAD and NEMO, dimerization assays, IFN reporters and viral replication readouts

    PMID:28392573 PMID:28468885

    Open questions at the time
    • Whether IRF3 and NEMO effects are independent or share a mechanism unclear
    • Single-lab Co-IP for each interaction
  6. 2019 High

    Connected Rubicon to organismal aging by showing age-dependent upregulation suppresses autophagy and that its loss extends lifespan and reduces fibrosis and proteinopathy.

    Evidence Cross-species protein/mRNA quantitation, RNAi lifespan assays in worm/fly, Rubicon KO mouse phenotyping

    PMID:30783089

    Open questions at the time
    • Transcriptional driver of age-dependent Rubicon induction not identified
    • Tissue-specific contributions to lifespan extension unresolved
  7. 2019 Medium

    Identified the first post-translational control of Rubicon activity, with HUNK kinase phosphorylating Rubicon to inhibit its autophagy-suppressive function.

    Evidence Co-IP, in vitro kinase assay, LC3B readouts

    PMID:31752345

    Open questions at the time
    • Phosphorylation site(s) not mapped
    • Single-lab study with limited mechanistic follow-up
  8. 2020 High

    Resolved the RH–Rab7-GTP crystal structure, revealing a zinc-cluster fold and a unique Rab-effector binding mode, and validated the interface functionally in cells.

    Evidence 2.8 Å X-ray crystallography, interface mutagenesis, autophagic flux and live-cell colocalization

    PMID:32632011

    Open questions at the time
    • Structure of the RUN domain–Vps34 interaction still lacking
    • Full-length Rubicon architecture not visualized
  9. 2020 High

    Established Rubicon as a substrate-selective gatekeeper of autophagy in metabolic and reproductive tissues, protecting PPARγ coactivators and GATA4 from autophagic degradation, and linked its expression to nutrient/hormonal control.

    Evidence Tissue-specific KO mice (adipocyte, Sertoli), substrate identification by Co-IP/MS, GABARAP binding, FXR ChIP-seq/promoter assays, rescue experiments

    PMID:32001325 PMID:32811819 PMID:34351902

    Open questions at the time
    • How Rubicon selects substrates from bulk autophagy unclear
    • Whether substrate protection requires Rubicon's Vps34-inhibitory activity untested
  10. 2020 High

    Showed Rubicon upregulation drives pathological autophagosome accumulation and autosis in cardiac ischemia/reperfusion, and that CARD9 acts through Rubicon to modulate cardiomyocyte autophagy.

    Evidence Cardiac Rubicon transgenic/KO mice, EM for autosis, autophagic flux and injury measurements, CARD9 KO and siRNA epistasis

    PMID:32248306 PMID:32364533

    Open questions at the time
    • Trigger for Rubicon induction during I/R undefined
    • Relationship between autosis and Rubicon's molecular activities incomplete
  11. 2021 High

    Defined RNA-level control of Rubicon, with METTL3/YTHDF1-mediated m6A modification stabilizing its mRNA to suppress autophagosome-lysosome fusion in fatty liver.

    Evidence m6A-seq, RIP assays, YTHDF1 Co-IP with mRNA, siRNA knockdown with flux/lipid readouts

    PMID:34547464

    Open questions at the time
    • Signals controlling METTL3 targeting of Rubicon mRNA unknown
    • Single-lab characterization
  12. 2022 Medium

    Revealed additional autophagy-independent roles in receptor recycling and a feedforward autophagic self-degradation loop of Rubicon during fasting.

    Evidence Cardiomyocyte- and adipose-specific KO mice, receptor recycling assays, fasting model, gene expression and autophagy inhibition

    PMID:34996972 PMID:35282767

    Open questions at the time
    • Mechanism by which Rubicon supports beta-1 adrenergic receptor recycling unclear
    • Receptor for autophagic Rubicon degradation not identified
  13. 2023 High

    Identified ubiquitin-mediated turnover (HECTD1 at K534) as a control point for Rubicon abundance and uncovered a novel ZRR endosomal complex through which Rubicon promotes inflammasome activation.

    Evidence Co-IP and site-specific ubiquitination assays, conditional HECTD1 KO mice, inflammasome proteomics, competitive binding assays with caspase-1/FliI, in vivo and human tissue validation

    PMID:36121967 PMID:37225719

    Open questions at the time
    • Whether HECTD1 and other ligases act on the same lysine network unclear
    • Structural basis of ZRR complex assembly undefined
  14. 2023 High

    Distinguished functionally opposite Rubicon isoforms, showing the short RUN-lacking RUBCN100 on early endosomes enhances VPS34/autophagy while full-length RUBCN130 suppresses it, refining how the RUN domain dictates activity.

    Evidence Alternative isoform identification, domain deletion, fractionation, VPS34/mTORC1 assays, B cell-specific KO mice

    PMID:37725663

    Open questions at the time
    • Regulation of alternative translation initiation unknown
    • Relative physiological abundance of isoforms across tissues unclear
  15. 2024 High

    Assigned Rubicon a positive role in exosome biogenesis via WIPI2d/ESCRT recruitment and demonstrated a TBK1-Rab7A Ser72 phospho-switch that releases Rubicon to permit mitophagy.

    Evidence RNAi screen, WIPI2d interactome MS, exosome/small-RNA sequencing in aged mice; in vitro TBK1 phosphorylation-binding assays grounded in structure, depolarization colocalization, Pacer KO mitophagy assays

    PMID:38728007 PMID:39174742

    Open questions at the time
    • How Rubicon switches between inhibitory and exosome-promoting roles unclear
    • Generality of the Rab7A phospho-switch beyond mitophagy untested
  16. 2025 High

    Extended ubiquitin control of Rubicon to LC3-associated phagocytosis, with ENKD1-TRIM21 mediating K48-linked degradation to relieve Rubicon's suppression of LAP.

    Evidence Co-IP of ENKD1/TRIM21/RUBCN, K48-linkage ubiquitination assay, ENKD1 KO macrophages and in vivo bacterial clearance

    PMID:41187080

    Open questions at the time
    • Whether TRIM21 and HECTD1 target overlapping residues unresolved
    • Signals activating ENKD1-TRIM21 axis undefined
  17. 2026 Medium

    Uncovered autophagy-independent functions of Rubicon in platelets, regulating phosphatidylserine exposure, collagen binding, and Btk-dependent thrombus formation, with therapeutic peptide proof-of-concept in stroke.

    Evidence Platelet/megakaryocyte-specific KO mice, FeCl3 thrombosis and microfluidic shear assays, Co-IP with Btk, Rubicon-Btk peptide in cerebral infarction model

    PMID:41259739 PMID:41566765

    Open questions at the time
    • Molecular mechanism linking Rubicon to phosphatidylserine exposure unknown
    • Single-lab findings for each platelet phenotype

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how Rubicon's many context-dependent activities—autophagy inhibition, substrate protection, exosome biogenesis, immune signaling, and platelet function—are coordinately switched within a single cell.
  • No structural model of full-length Rubicon integrating RUN and RH domains
  • No unifying regulatory logic connecting its opposing roles
  • Selectivity determinants for autophagic substrate protection unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005768 endosome 5 GO:0005764 lysosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-9612973 Autophagy 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3
Partners
BTKCARD9IRF3P22PHOXPIK3C3/VPS34RAB7AUVRAGWIPI2D
Complex memberships
Beclin 1-Vps34 (Class III PI3K) UVRAG complexZRR complex (ZFYVE21-Rubicon-RNF34)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Rubicon was identified as a component of the Beclin 1-hVps34 (Class III PI3K) complex, associating specifically with a subpopulation of UVRAG-containing complexes (but not Atg14L complexes), defining three distinct Beclin 1 complexes. GFP-Rubicon localizes to late endosomes/lysosomes. Knockdown of Rubicon enhances autophagy at the maturation step and enhances endocytic trafficking, establishing Rubicon as a negative regulator of autophagosome maturation and endocytic trafficking. Co-immunoprecipitation/mass spectrometry, GFP-fusion localization imaging, siRNA knockdown with autophagy and endocytic flux readouts Nature cell biology High 19270696
2009 Rubicon reduces Vps34 lipid kinase activity in vitro and downregulates autophagy. Forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. Rubicon is part of a large in vivo Beclin 1 complex containing Vps34, p150/Vps15, and UVRAG. In vitro PI3K lipid kinase assay, overexpression and mouse genetics combined with biochemistry, fluorescence microscopy Nature cell biology High 19270693
2010 Rubicon acts as a Rab7 effector that prevents endosome maturation by sequestering UVRAG away from the C-VPS/HOPS complex (a GEF for Rab7). Active GTP-bound Rab7 competes for Rubicon binding and releases UVRAG to associate with HOPS, creating a feed-forward loop for Rab7-GTP amplification and endosome maturation. Co-immunoprecipitation, pulldown assays, dominant-negative and constitutively active Rab7 constructs, endosome maturation assays Proceedings of the National Academy of Sciences of the United States of America High 20974968
2010 Rubicon and PLEKHM1 share a C-terminal RH domain that directly binds Rab7, and this interaction is required for their inhibitory function on endocytic/autophagic trafficking. Rubicon uniquely also binds PI3-kinase simultaneously via its RH domain, whereas PLEKHM1 does not. Knockdown of Rubicon suppresses endocytic transport; Rubicon but not PLEKHM1 suppresses autophagosome maturation. Database homology search, direct binding assays (pulldown), deletion mutagenesis, siRNA knockdown with trafficking readouts Molecular biology of the cell High 20943950
2010 The RUN domain of Rubicon is required for binding to the PI3KC3 catalytic subunit hVps34 and for efficient inhibition of hVps34 lipid kinase activity. A RUN domain deletion mutant fails to rescue autophagy deficiency in Rubicon-depleted cells, establishing the RUN domain as essential for PI3KC3 and autophagy regulation. Co-immunoprecipitation, in vitro PI3K lipid kinase assay, RUN-domain deletion mutagenesis, complementation assay in Rubicon-knockdown cells The Journal of biological chemistry High 21062745
2012 Upon microbial infection or TLR2 stimulation, Rubicon interacts with the p22phox subunit of the NADPH oxidase complex, facilitating phagosomal trafficking of the NOX complex to induce a burst of reactive oxygen species (ROS) and inflammatory cytokines. Ectopic expression or depletion of Rubicon profoundly affects ROS production, inflammatory cytokine production, and antimicrobial activity. The autophagy and NADPH oxidase functions of Rubicon are genetically separable. Co-immunoprecipitation of Rubicon with p22phox, overexpression and siRNA knockdown with ROS measurement, cytokine assays, microbial killing assays Cell host & microbe High 22423966
2012 Rubicon acts as a physiological feedback inhibitor of CARD9-BCL10-MALT1 (CBM) complex-mediated PRR signaling. Upon Dectin-1 or RIG-I activation, Rubicon dynamically exchanges binding partners from 14-3-3β to CARD9 in a stimulation-specific and phosphorylation-dependent manner, disassembling the CBM signaling complex and terminating PRR-induced cytokine production. Co-immunoprecipitation, phosphorylation-dependent binding assays, overexpression and knockdown with cytokine readouts, genetic epistasis Cell host & microbe High 22423967
2013 KSHV K7 protein interacts with Rubicon and inhibits autophagosome maturation by blocking Vps34 enzymatic activity. Co-immunoprecipitation of K7 with Rubicon, Vps34 kinase assay, autophagosome maturation assay Journal of virology Medium 24027317
2013 The Salih ataxia frameshift mutation in RUBCN (deletion of diacylglycerol binding-like motif in C-terminal RH domain) causes diffuse cytosolic distribution of Rubicon and mislocalization away from late endosomes, confirming that the C-terminal RH domain is required for proper Rubicon subcellular localization to late endosomes/lysosomes (marked by Rab7 and LAMP1). Fluorescence microscopy of mutant vs. wild-type Rubicon in cultured cells, colocalization with Rab7 and LAMP1 Cerebellum (London, England) Medium 23728897
2017 Rubicon interacts with the IRF association domain (IAD) of IRF3 and inhibits IRF3 dimerization, thereby negatively regulating IFN-mediated antiviral response. Knockdown of Rubicon promotes type I interferon signaling and inhibits virus replication. Co-immunoprecipitation of Rubicon with IRF3, IRF3 dimerization assays, siRNA knockdown with IFN reporter assays and viral replication readouts Journal of virology Medium 28468885
2017 Rubicon interacts with NEMO (NF-κB essential modulator), inhibiting ubiquitination of NEMO and thereby suppressing type I and type III interferon production during viral infection. Rubicon expression was induced by HBV infection and promoted viral replication. Co-immunoprecipitation of Rubicon with NEMO, overexpression and knockdown with IFN production readouts, viral replication assays Cellular & molecular immunology Medium 28392573
2019 Rubicon expression increases with age in worm, fly, and mouse tissues; age-dependent upregulation of Rubicon suppresses autophagic activity. Knockdown of Rubicon in C. elegans and Drosophila extends lifespan and ameliorates age-associated phenotypes. In mice, Rubicon knockout reduces interstitial fibrosis in kidney and α-synuclein accumulation in brain. Rubicon is suppressed in long-lived worms and calorie-restricted mice. Quantitative protein/mRNA analysis across species, RNAi knockdown lifespan assays, Rubicon KO mouse phenotyping including histology and immunohistochemistry Nature communications High 30783089
2019 HUNK kinase binds to and phosphorylates Rubicon; phosphorylation of Rubicon by HUNK inhibits Rubicon's autophagy-suppressive function, promoting autophagy. Co-immunoprecipitation, in vitro kinase assay, LC3B immunofluorescence and immunoblotting International journal of molecular sciences Medium 31752345
2020 Crystal structure of the Rubicon RH domain in complex with Rab7-GTP at 2.8 Å resolution reveals that the RH domain is built around four zinc clusters and that the switch regions of Rab7 insert into pockets on the RH domain surface in a mode distinct from other Rab-effector complexes. Mutation of RH residues at the Rab7-binding site restores autophagic flux in the presence of overexpressed Rubicon. Rubicon residues at the dimer interface are required for Rubicon-Rab7 colocalization in living cells. X-ray crystallography (2.8 Å), site-directed mutagenesis, autophagic flux assays, live-cell colocalization imaging Proceedings of the National Academy of Sciences of the United States of America High 32632011
2020 CARD9 interacts directly with Rubicon and enhances UVRAG-Beclin1-PI3KC3 interaction and UVRAG-Vps16-mediated Rab7 activation, thereby promoting autophagosome formation, maturation, and endocytosis. siRNA ablation of Rubicon prevents the detrimental effect of CARD9 knockdown on cardiomyocytes during ischemia/reperfusion. Co-immunoprecipitation of CARD9 with Rubicon, CARD9 KO mice, siRNA knockdown, LC3 lipidation and p62 assays, Rab7 activation assay Basic research in cardiology Medium 32248306
2020 Rubicon upregulation during myocardial ischemia/reperfusion attenuates autophagic flux, leading to marked autophagosome accumulation and autosis (a form of autophagy-dependent cell death). Genetic downregulation of Rubicon inhibits autosis and reduces I/R injury. Rubicon upregulation is mechanistically linked to dysregulated autophagosome accumulation. Rubicon transgenic overexpression and knockout in cardiomyocytes, electron microscopy for autosis morphology, autophagic flux assays, cardiac injury measurements The Journal of clinical investigation High 32364533
2020 In aged adipocytes, Rubicon levels decline, leading to excess autophagy that degrades SRC-1 (NCOA1) and TIF2 (NCOA2), coactivators of PPARγ, via their binding to GABARAP family proteins. This causes fat atrophy and hepatic lipid accumulation. The metabolic phenotype is rescued by PPARγ activation. Adipocyte-specific Rubicon KO mice, PPARγ rescue experiments, autophagic substrate identification by Co-IP and MS, GABARAP binding assay Nature communications High 32811819
2020 FXR (farnesoid X receptor) directly binds to the Rubicon promoter and induces Rubicon expression in response to bile acids, as demonstrated by FXR ChIP-seq and luciferase promoter assays. FXR-induced Rubicon expression inhibits autophagosome-lysosome fusion and blocks autophagic flux. Genetic inhibition of Rubicon reverses bile acid-induced impairment of autophagic flux. FXR ChIP-seq, luciferase promoter assay, siRNA knockdown, autophagic flux assays Journal of hepatology High 32001325
2021 METTL3 directly binds to Rubicon mRNA and mediates m6A modification; YTHDF1 interacts with the m6A-marked Rubicon mRNA and promotes its stability, leading to increased Rubicon protein levels and inhibition of autophagosome-lysosome fusion in NAFLD. Knockdown of METTL3 or YTHDF1 promotes autophagic flux and reduces lipid accumulation. m6A-seq, RIP assay (METTL3 binding to Rubicon mRNA), YTHDF1 Co-IP with Rubicon mRNA, siRNA knockdown with autophagic flux and lipid readouts Molecular therapy : the journal of the American Society of Gene Therapy High 34547464
2021 Rubicon prevents autophagic degradation of GATA4 (a transcription factor essential for Sertoli cell function). Rubicon knockout in Sertoli cells (but not germ cells) causes defective spermatogenesis and germline stem cell maintenance. Androgen antagonists decrease Rubicon and GATA4 in testis, accompanied by elevated autophagy. Sertoli cell-specific Rubicon KO mice, autophagic flux assays, GATA4 protein level measurement after Rubicon KO, androgen antagonist treatment PLoS genetics High 34351902
2022 Rubicon regulates the recycling of beta-1 adrenergic receptor in cardiomyocytes. Cardiomyocyte-specific Rubicon deficiency accelerates agonist-induced receptor downregulation through inhibition of receptor recycling, leading to heart failure with left ventricular dilatation and systolic dysfunction under pressure overload. Cardiomyocyte-specific Rubicon KO mice, transverse aortic constriction model, beta-1 adrenergic receptor protein levels and recycling assays, siRNA in neonatal rat cardiomyocytes, echocardiography Scientific reports Medium 34996972
2022 Fasting causes degradation of Rubicon through autophagy in adipocytes, establishing a feedforward system: autophagic degradation of Rubicon further promotes autophagy. Loss of adipose Rubicon during fasting promotes autophagic degradation of NCOA1/SRC-1 and NCOA2/TIF2 (coactivators of PPARγ), reducing mRNA levels of adipogenic genes and promoting fat loss and hepatic steatosis during fasting. Adipose-specific rubcn-knockout mice, fasting model, autophagic flux assays, gene expression analysis, genetic inhibition of autophagy in adipocytes Autophagy High 35282767
2023 HECTD1 E3 ubiquitin ligase binds Rubicon and ubiquitinates it at lysine residue 534, targeting Rubicon for proteasomal degradation. HECTD1-mediated Rubicon degradation regulates chondrocyte autophagy. HECTD1 is downregulated in OA cartilage, leading to Rubicon accumulation and autophagy suppression. Co-immunoprecipitation of HECTD1 with Rubicon, ubiquitination assay identifying K534 site, proteasome inhibitor experiments, HECTD1 overexpression and conditional KO in mice Arthritis & rheumatology (Hoboken, N.J.) High 36121967
2023 Rubicon forms a 'ZRR' complex with ZFYVE21 (a Rab5 effector) and RNF34 on early endosomes in endothelial cells. Within this complex, Rubicon competitively disrupts inhibitory associations between caspase-1 and Flightless I (FliI), increasing pools of endosome-associated active caspase-1. RNF34 ubiquitinates and removes FliI from the signaling endosome. This complex promotes NLRP3 inflammasome activity following complement MAC internalization. Proteomic analysis of FACS-sorted inflammasomes, Co-IP of ZFYVE21/Rubicon/RNF34, competitive binding assays for Rubicon-FliI-caspase-1, in vivo mouse models, human tissue validation Nature communications High 37225719
2023 RUBCN expresses a shorter isoform RUBCN100 translated from alternative initiation sites, lacking the RUN domain. RUBCN100 localizes to early endosomes (unlike RUBCN130 on late endosomes/lysosomes), enhances VPS34 activity and autophagy, and suppresses mTORC1 activation. RUBCN130 (full-length) suppresses VPS34 activity via its RUN domain. Specific deficiency of RUBCN130 in B cells enhances autophagy and promotes memory B cell generation. Alternative isoform identification, domain deletion constructs, subcellular fractionation/localization, VPS34 kinase assays, mTORC1 activity assays, B cell-specific KO mice Science signaling High 37725663
2024 Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified ESCRT components required for intraluminal vesicle formation. Rubicon is required for age-dependent increases in exosome release in mice. Rubicon determines the composition of exosomal microRNAs (including Mir26a and Mir486a) associated with cellular senescence. Comprehensive RNAi screen, WIPI2d interactome analysis (MS), exosome isolation and quantification, small RNA sequencing of serum exosomes, aged mouse models Nature cell biology High 39174742
2024 TBK1-dependent phosphorylation of RAB7A at Ser72 abrogates Rubicon:RAB7A binding in vitro. In cells, mitochondrial depolarization reduces Rubicon:RAB7A colocalization. This phospho-switch relieves Rubicon inhibition of autophagy, favoring Pacer (positive autophagy regulator) binding to phospho-RAB7A to promote Parkin-dependent mitophagy. In vitro phosphorylation by TBK1 followed by binding assay, structural analysis of Rubicon RH:RAB7A complex, live-cell colocalization upon mitochondrial depolarization, Pacer KO cells with mitophagy assays The Journal of cell biology High 38728007
2025 ENKD1 interacts with E3 ubiquitin ligase TRIM21, which mediates K48-linked polyubiquitination and degradation of RUBCN, thereby dampening RUBCN's role in LC3-associated phagocytosis. ENKD1-deficient macrophages show enhanced LAP, ROS production, LC3 lipidation on phagosomes, and improved phagosome-lysosome fusion. Co-immunoprecipitation of ENKD1 with TRIM21 and RUBCN, ubiquitination assay (K48-linkage), ENKD1 KO macrophages, LAP assays, in vivo bacterial clearance in ENKD1-KO mice Proceedings of the National Academy of Sciences of the United States of America High 41187080
2026 In platelets, Rubicon plays an autophagy-independent role in arterial thrombosis. Platelet/megakaryocyte-specific RUBCN deletion impairs phosphatidylserine surface exposure after thrombin and convulxin activation, reduces collagen binding under high shear flow, and causes a significant thrombosis defect in vivo, without affecting canonical platelet activation, granule secretion, or autophagic flux. Platelet-specific RUBCN KO mice, FeCl3 carotid injury model, microfluidics shear flow assay, phosphatidylserine exposure (annexin V), platelet aggregation, autophagic flux assays Blood advances Medium 41259739
2026 Rubicon interacts with Bruton's tyrosine kinase (Btk) to inhibit GPVI-mediated thrombus formation in platelets; separately, Rubicon prevents αIIbβ3-mediated selective autophagy and degradation of Btk, thereby stabilizing platelet thrombi. A cell-permeable peptide mimicking the Rubicon-Btk interaction reduces cerebral infarction volume in mice. Co-immunoprecipitation of Rubicon with Btk, megakaryocyte-platelet-specific Rubicon KO mice, autophagy assays, Rubicon-Btk peptide in stroke model Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 41566765

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nature cell biology 992 19270696
2009 Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nature cell biology 820 19270693
2016 Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology (Baltimore, Md.) 296 27637015
2010 Rubicon controls endosome maturation as a Rab7 effector. Proceedings of the National Academy of Sciences of the United States of America 199 20974968
2019 Suppression of autophagic activity by Rubicon is a signature of aging. Nature communications 166 30783089
2000 Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists. Human reproduction (Oxford, England) 138 10831542
2012 Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation. Cell host & microbe 136 22423966
2010 Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain. Molecular biology of the cell 131 20943950
2020 Upregulation of Rubicon promotes autosis during myocardial ischemia/reperfusion injury. The Journal of clinical investigation 126 32364533
2010 The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression. The Journal of biological chemistry 116 21062745
2015 HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLoS pathogens 111 25807108
2021 METTL3-m6A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease. Molecular therapy : the journal of the American Society of Gene Therapy 104 34547464
2012 The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity. Cell host & microbe 92 22423967
2007 Bridging the Rubicon: phylogenetic analysis reveals repeated colonizations of marine and fresh waters by thalassiosiroid diatoms. Molecular phylogenetics and evolution 86 17553708
2020 CARD9 promotes autophagy in cardiomyocytes in myocardial ischemia/reperfusion injury via interacting with Rubicon directly. Basic research in cardiology 84 32248306
2020 Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy. Nature communications 74 32811819
2013 Kaposi's sarcoma-associated herpesvirus K7 modulates Rubicon-mediated inhibition of autophagosome maturation. Journal of virology 71 24027317
2002 Rubicon Genomics, Inc. Pharmacogenomics 62 12164778
2020 FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis. Journal of hepatology 61 32001325
2020 Podocyte EGFR Inhibits Autophagy Through Upregulation of Rubicon in Type 2 Diabetic Nephropathy. Diabetes 61 33239448
2017 RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye. Autophagy 57 28933590
2023 HECTD1-Mediated Ubiquitination and Degradation of Rubicon Regulates Autophagy and Osteoarthritis Pathogenesis. Arthritis & rheumatology (Hoboken, N.J.) 47 36121967
2022 LC3-associated endocytosis and the functions of Rubicon and ATG16L1. Science advances 47 36288306
2017 Inducible Rubicon facilitates viral replication by antagonizing interferon production. Cellular & molecular immunology 38 28392573
2009 Binding Rubicon to cross the Rubicon. Autophagy 38 19550146
2010 Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia. Brain : a journal of neurology 37 20826435
2015 Rubicon swaps autophagy for LAP. Nature cell biology 36 26123110
2020 Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells. Autophagy 34 31944172
2017 Rubicon Modulates Antiviral Type I Interferon (IFN) Signaling by Targeting IFN Regulatory Factor 3 Dimerization. Journal of virology 34 28468885
2003 Nutrigenomics: the Rubicon of molecular nutrition. Journal of the American Dietetic Association 31 14666500
2020 Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex. Proceedings of the National Academy of Sciences of the United States of America 30 32632011
2022 Loss of RUBCN/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response. Autophagy 29 35282767
2015 Rubicon deficiency enhances cardiac autophagy and protects mice from lipopolysaccharide-induced lethality and reduction in stroke volume. Journal of cardiovascular pharmacology 28 25502307
2024 A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy. The Journal of cell biology 24 38728007
2024 The Rubicon-WIPI axis regulates exosome biogenesis during ageing. Nature cell biology 24 39174742
2022 Rubicon promotes the M2 polarization of Kupffer cells via LC3-associated phagocytosis-mediated clearance to improve liver transplantation. Cellular immunology 24 35700602
2020 Hepatitis C virus enhances Rubicon expression, leading to autophagy inhibition and intracellular innate immune activation. Scientific reports 23 32943718
2021 The roles of the inhibitory autophagy regulator Rubicon in the heart: A new therapeutic target to prevent cardiac cell death. Experimental & molecular medicine 22 33854187
2021 Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function. PLoS genetics 22 34351902
2019 RUBCNL/Pacer and RUBCN/Rubicon in regulation of autolysosome formation and lipid metabolism. Autophagy 22 30894088
2019 Loss of Rubicon ameliorates doxorubicin-induced cardiotoxicity through enhancement of mitochondrial quality. International journal of cardiology 22 31439425
2019 Rubicon-Dependent Lc3 Recruitment to Salmonella-Containing Phagosomes Is a Host Defense Mechanism Triggered Independently From Major Bacterial Virulence Factors. Frontiers in cellular and infection microbiology 21 31428591
2020 Crossing the Vacuolar Rubicon: Structural Insights into Effector Protein Trafficking in Apicomplexan Parasites. Microorganisms 20 32521667
2013 The Salih ataxia mutation impairs Rubicon endosomal localization. Cerebellum (London, England) 19 23728897
2016 Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock. Biomaterials 18 27267627
2022 Rubicon in Metabolic Diseases and Ageing. Frontiers in cell and developmental biology 17 35083223
2021 Acanthopanax senticosus Harms extract causes G0/G1 cell cycle arrest and autophagy via inhibition of Rubicon in human liver cancer cells. Oncology reports 17 33650674
2020 Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15). BMC neurology 16 32450808
2019 HUNK Phosphorylates Rubicon to Support Autophagy. International journal of molecular sciences 15 31752345
2016 c-Jun N-terminal kinase-mediated Rubicon expression enhances hepatocyte lipoapoptosis and promotes hepatocyte ballooning. World journal of gastroenterology 15 27605885
2024 Lipid Nanoparticle-Mediated Delivery of CRISPR-Cas9 Against Rubicon Ameliorates NAFLD by Modulating CD36 Along with Glycerophospholipid Metabolism. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 38894572
2022 A Combination therapy using an mTOR inhibitor and Honokiol effectively induces autophagy through the modulation of AXL and Rubicon in renal cancer cells and restricts renal tumor growth following organ transplantation. Carcinogenesis 12 34965300
2024 RUBICON: a framework for designing efficient deep learning-based genomic basecallers. Genome biology 11 38365730
2023 CX3CL1 represses autophagy via CX3CR1/ CaMKIIδ/HDAC4/Rubicon axis and exacerbates chronic intermittent hypoxia induced Kupffer cell apoptosis. Cellular signalling 11 37640194
2022 Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis. JCI insight 11 35192551
2025 Interplay of Oxidative Stress, Autophagy, and Rubicon in Ovarian Follicle Dynamics: Orchestrating Ovarian Aging. Antioxidants (Basel, Switzerland) 10 40867818
2022 Inhibition of interaction between ROCK1 and Rubicon restores autophagy in endothelial cells and attenuates brain injury after prolonged ischemia. Journal of neurochemistry 8 36334306
2016 Protein trafficking in apicomplexan parasites: crossing the vacuolar Rubicon. Current opinion in microbiology 8 27155394
2025 Rubicon, a Key Molecule for Oxidative Stress-Mediated DNA Damage, in Ovarian Granulosa Cells. Antioxidants (Basel, Switzerland) 7 40298803
2023 Opposing roles of RUBCN isoforms in autophagy and memory B cell generation. Science signaling 7 37725663
2022 Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury. Cell death & disease 7 35288534
2021 Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice. Antioxidants (Basel, Switzerland) 7 34943057
2023 A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells. Nature communications 6 37225719
2023 Reduction in Rubicon by cigarette smoke is associated with impaired phagocytosis and occurs through lysosomal degradation pathway. Clinical and experimental medicine 6 37310658
2022 Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload. Scientific reports 6 34996972
2022 DJ-1 binds to Rubicon to Impair LC-3 Associated Phagocytosis. Cell death and differentiation 6 35641782
2022 Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer's Disease. Cells 6 35740989
2022 Clinical application of RUBCN/SESN2 mediated inhibition of autophagy as biomarkers of diabetic kidney disease. Molecular medicine (Cambridge, Mass.) 6 36476132
2020 Rubicon in pancreatic beta cells plays a limited role in maintaining glucose homeostasis following increased insulin resistance. Endocrine journal 6 32669482
2012 Crossing the Rubicon: new roads lead to host defense. Cell host & microbe 6 22423961
2024 The marine-derived compound TAG alleviates Parkinson's disease by restoring RUBCN-mediated lipid metabolism homeostasis. Acta pharmacologica Sinica 5 38538717
2024 Rubicon regulates exosome secretion via the non-autophagic pathway. Autophagy 5 39667388
2025 SuoquanYishen formula improves renal cellular senescence by inhibiting YTHDF1-Rubicon axis to promote autophagy in diabetic kidney disease. Frontiers in pharmacology 4 40371338
2025 Rubicon siRNA-encapsulated liver-targeting nanoliposome is a promising therapeutic for non-alcoholic fatty liver disease. International journal of pharmaceutics 3 39880145
2024 All-trans retinoic acid induces lipophagy through the activation of the AMPK-Beclin1 signaling pathway and reduces Rubicon expression in adipocytes. The Journal of nutritional biochemistry 3 38295886
2024 Circulating autophagy regulator Rubicon is linked to increased myocardial infarction risk. Journal of molecular and cellular cardiology plus 3 39802263
2024 Plasma levels of autophagy regulator Rubicon are inversely associated with acute coronary syndrome. Frontiers in cardiovascular medicine 2 38250026
2023 Crossing the Solubility Rubicon: 15-Crown-5 Facilitates the Preparation of Water-Soluble Sulfo-NHS Esters in Organic Solvents. Bioconjugate chemistry 2 38086083
2021 Dataset on the effect of Rubicon overexpression on polyglutamine-induced locomotor dysfunction in Drosophila. Data in brief 2 34189208
2026 Role of Rubicon in platelets: a promoter of thrombosis but not an autophagy repressor. Blood advances 1 41259739
2025 [Advances in the study of viruses inhibiting the production of advanced autophagy or interferon through Rubicon to achieve innate immune escape]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 39799430
2025 ENKD1 attenuates antibacterial immunity by facilitating TRIM21-mediated RUBCN degradation to suppress LC3-associated phagocytosis. Proceedings of the National Academy of Sciences of the United States of America 1 41187080
2024 A second RUBCN variant associated with epileptic encephalopathy and neurodevelopmental delay. American journal of medical genetics. Part A 1 39520129
2026 Platelet Rubicon Bidirectional Regulation of GPVI and Integrin αIIbβ3 Signaling Mitigates Stroke Infarction Without Compromising Hemostasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41566765
2026 Rubicon modulates neuroimmune responses following traumatic brain injury. bioRxiv : the preprint server for biology 0 41867877
2025 MAB_0676c-induced enhanced IL-10 production inhibits the autophagic flux via the MTOR/RUBCN pathway. Virulence 0 40641107
2025 Salvianic acid A promotes osteogenic differentiation of bone marrow mesenchymal stem cells in senile osteoporosis through bromodomain-containing protein 4/Ariadne RBR E3 ubiquitin-protein ligase 1/Rubicon axis. Journal of traditional and complementary medicine 0 40677544
2025 Neoadjuvant chemoimmunotherapy or chemoradiotherapy in stage III non-small cell lung cancer: crossing the Rubicon? Chinese clinical oncology 0 41208422
2025 The monkeypox virus suppresses autophagy by modulating Rubicon expression. Cell death discovery 0 41436430
2024 All-trans retinoic acid induces lipophagy by reducing Rubicon in Hepa1c1c7 cells. Journal of lipid research 0 39032560
2024 WSSV induces Rubicon expression to regulate innate immune response in Penaeus vannamei. Fish & shellfish immunology 0 39571631

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