Affinage

RC3H1

Roquin-1 · UniProt Q5TC82

Length
1133 aa
Mass
125.7 kDa
Annotated
2026-04-28
80 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RC3H1 (Roquin-1) is an RNA-binding E3 ubiquitin ligase that post-transcriptionally represses proinflammatory and costimulatory mRNAs—including ICOS, OX40, TNF-α, IL-6, TfR1, and IRF1—by recognizing constitutive and alternative decay element (CDE/ADE) stem-loops and AU-rich sequences in 3′ UTRs via its bimodal ROQ domain (A-site for apical stem-loops, B-site for double-stranded RNA) and CCCH-type zinc finger, then recruiting the CCR4-NOT deadenylase complex and decapping machinery at P-bodies to trigger mRNA degradation (PMID:18172933, PMID:23663784, PMID:25026078, PMID:38953172, PMID:27010430). Roquin-1 physically cooperates with Regnase-1 on overlapping target mRNAs but acts on translationally inactive transcripts at P-bodies and stress granules, whereas Regnase-1 degrades ribosome-associated mRNAs; both are inactivated by MALT1-mediated proteolytic cleavage in a TCR signal-strength-graded manner that tunes T helper cell differentiation (PMID:26000482, PMID:25282160, PMID:37988467, PMID:34811541). The RING domain confers E3 ubiquitin ligase activity that antagonizes AMPK to promote T follicular helper cell differentiation and mediates GPX4 ubiquitination to regulate ferroptosis (PMID:26496200, PMID:39739814). A homozygous human loss-of-function RC3H1 mutation (R688*) causes hyperinflammation due to impaired P-body localization and CCR4-NOT recruitment (PMID:31636267).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2007 High

    Establishing that Roquin-1 controls immune homeostasis by limiting ICOS mRNA stability through its ROQ domain answered the foundational question of why sanroque mice develop lupus-like autoimmunity.

    Evidence Genetic analysis of M199R sanroque mice with ICOS 3′ UTR functional dissection and mRNA decay assays

    PMID:18172933

    Open questions at the time
    • Precise RNA element recognized by Roquin not yet defined
    • Effector machinery recruited by Roquin unknown
    • Whether Roquin directly binds ICOS mRNA not established
  2. 2010 High

    Demonstrating that Roquin directly binds ICOS mRNA at P-bodies and requires the decapping machinery (Rck, Edc4) but not the miRNA/RISC pathway defined Roquin as a miRNA-independent post-transcriptional repressor acting through mRNA decapping.

    Evidence Co-IP, fluorescence microscopy of P-body localization, RNA binding assays, Ago2/RISC decoupling in cell-based assays

    PMID:20412057 PMID:20639877

    Open questions at the time
    • Identity of the cis-regulatory RNA element beyond the ICOS 3′ UTR region not resolved
    • Mechanism linking P-body localization to mRNA decay not defined
  3. 2013 High

    Identification of the constitutive decay element (CDE) stem-loop as a conserved Roquin-recognition motif in >50 mRNAs, and demonstration that Roquin recruits the CCR4-CAF1-NOT deadenylase complex, established the core effector mechanism and broadened the target repertoire beyond ICOS.

    Evidence RNA-protein binding assays, mRNA decay assays in macrophages, deadenylase recruitment assays, transcriptome-wide CDE identification; concurrent genetic KO studies showing Roquin-1/2 redundancy

    PMID:23583643 PMID:23663784

    Open questions at the time
    • Structural basis of CDE recognition unknown
    • Whether Roquin recognizes non-CDE elements not addressed
    • Mechanism of CCR4-NOT recruitment not defined at atomic level
  4. 2014 High

    Crystal structures of the ROQ domain bound to CDE RNA revealed a winged-helix fold with two distinct RNA-binding surfaces (A-site for stem-loops, B-site for dsRNA), explaining how Roquin achieves broad yet specific target recognition.

    Evidence X-ray crystallography of mouse and human ROQ domains (multiple structures), NMR, mutagenesis with cell-based mRNA decay readouts

    PMID:25026077 PMID:25026078 PMID:25504471

    Open questions at the time
    • Role of the B-site in vivo not established
    • Contribution of non-ROQ domains to target selection not defined
    • Stoichiometry of Roquin on natural 3′ UTRs unknown
  5. 2014 High

    Discovery that MALT1 protease cleaves both Roquin-1 and Regnase-1 upon TCR stimulation answered how antigen receptor signaling releases post-transcriptional repression of inflammatory mRNAs to permit T helper differentiation.

    Evidence Biochemical cleavage assays, T cell genetic models, mRNA reporter assays

    PMID:25282160

    Open questions at the time
    • Whether cleavage is graded with signal strength not yet shown
    • Relative contributions of Roquin vs. Regnase-1 inactivation not dissected
  6. 2015 High

    Defining that Roquin and Regnase-1 repress overlapping mRNAs but in distinct subcellular compartments—Roquin on translationally inactive mRNAs at P-bodies/stress granules, Regnase-1 on ribosome-associated mRNAs—resolved how two seemingly redundant repressors achieve complementary surveillance.

    Evidence Subcellular fractionation, ribosome profiling, UPF1 requirement assays, mRNA decay assays

    PMID:26000482

    Open questions at the time
    • How targets are partitioned between compartments not explained
    • Whether Roquin-Regnase-1 physical interaction is required for this compartmentalization unknown
  7. 2015 High

    PAR-CLIP revealed ~3,800 RC3H1 mRNA targets genome-wide including A20, and showed that both the ROQ and zinc finger domains contribute to RNA binding, while the RING domain was shown to antagonize AMPK to specifically promote Tfh differentiation, establishing a second, non-RNA-decay function for Roquin.

    Evidence PAR-CLIP transcriptome-wide, domain mutagenesis with NF-κB pathway assays; conditional RING-domain KO mice with AMPK interaction assays

    PMID:26170170 PMID:26496200

    Open questions at the time
    • RING domain substrates beyond AMPK unknown
    • How RNA-binding and E3 ligase functions are coordinated unclear
  8. 2016 High

    Discovery of the alternative decay element (ADE) hexaloop as a second class of Roquin target motif, bound via the same ROQ domain interface as CDEs, expanded the Roquin target code and explained cooperative repression of Ox40 through tandem CDE+ADE elements.

    Evidence SELEX, X-ray crystallography of ROQ-ADE complex, NMR, cell-based repression assays

    PMID:27010430

    Open questions at the time
    • Genome-wide prevalence of ADE motifs not mapped
    • How CDE and ADE elements cooperate quantitatively in full-length 3′ UTRs not defined
  9. 2017 High

    Structural characterization of how Roquin recruits the CCR4-NOT complex via a C-terminal CAF40-binding motif (CBM) provided the atomic-level mechanism for deadenylation-dependent mRNA decay.

    Evidence X-ray crystallography of Drosophila Roquin CBM–CAF40 complex, Co-IP, binding assays

    PMID:28165457

    Open questions at the time
    • Whether human Roquin-1 uses an identical CBM interface not structurally confirmed
    • Contribution of CBM vs. other CCR4-NOT contacts not dissected in vivo
  10. 2018 High

    iCLIP and reporter studies showed that Roquin binds both structured and linear sequence elements, and that multiple Roquin molecules cooperatively occupy tandem sites on a single 3′ UTR to achieve both deadenylation/decapping and translational repression, revealing dose-dependent regulatory modes.

    Evidence iCLIP, polysome profiling, deadenylation/decapping mutant rescue assays

    PMID:29352114 PMID:30232334

    Open questions at the time
    • Structural basis of NUFIP2 cofactor cooperation with Roquin not resolved
    • In vivo stoichiometry on endogenous targets not measured
  11. 2019 High

    A human homozygous R688* RC3H1 mutation causing hyperinflammation established that Roquin-1 is essential for immune homeostasis in humans, and that the C-terminal region is required for P-body localization and CCR4-NOT interaction.

    Evidence Patient genetic analysis, P-body localization assays, CCR4-NOT Co-IP, mRNA decay assays

    PMID:31636267

    Open questions at the time
    • Additional human disease-causing alleles not reported
    • Whether Roquin-2 partially compensates in the patient not assessed
  12. 2021 High

    Mapping the direct Roquin-1–Regnase-1 physical interaction surface (including M199) demonstrated that their cooperation is not merely functional overlap but requires direct protein–protein contact, explaining why the sanroque mutation disrupts both partners' function.

    Evidence Co-IP, interaction surface mapping, conditional KO mice with autoimmune phenotyping

    PMID:34811541

    Open questions at the time
    • Structural model of the Roquin–Regnase-1 complex not available
    • Whether interaction is RNA-dependent not resolved
  13. 2021 High

    Identification of transferrin receptor 1 (TfR1) mRNA as a Roquin target connected Roquin to iron homeostasis and metabolism beyond inflammation, with osteoclast-specific KO revealing bone loss due to increased iron uptake and mitochondrial respiration.

    Evidence Gene KO in multiple cell types, 3′ UTR mutational analysis, osteoclast-specific conditional KO with Tfr1 rescue

    PMID:33898949 PMID:39659568

    Open questions at the time
    • Whether iron status feeds back to regulate Roquin expression unknown
    • Relative contribution of Roquin vs. IRP/IRE system to TfR1 regulation in vivo not quantified
  14. 2023 High

    Knock-in cleavage-resistant Roquin-1 (Mins) mice proved that MALT1-mediated cleavage is the dominant mechanism inactivating Roquin downstream of TCR, and that graded cleavage creates a signal-strength decoder for differential target mRNA derepression.

    Evidence Rc3h1Mins/Mins knock-in mice, genetic epistasis with constitutively active MALT1, EAE disease model, Th17 assays

    PMID:37988467

    Open questions at the time
    • Whether other proteases contribute to Roquin inactivation in non-T cells not addressed
    • Quantitative relationship between cleavage fraction and individual target derepression not modeled
  15. 2024 High

    Discovery that Roquin-1 functions as an E3 ubiquitin ligase targeting GPX4 for degradation, triggered by MALT1 inhibition, connected Roquin to ferroptosis regulation in cancer and revealed a non-RNA-decay effector axis.

    Evidence Genome-wide CRISPR screen, ubiquitination assays, ferroptosis readouts in liver cancer cells

    PMID:39739814

    Open questions at the time
    • Whether GPX4 ubiquitination depends on the RING domain specifically not shown
    • Breadth of E3 ligase substrates beyond AMPK and GPX4 unknown
    • In vivo relevance of the MALT1-Roquin-GPX4 axis in tumors not established
  16. 2024 High

    NMR structure of the CCCH zinc finger revealed it recognizes AU-rich linear RNA sequences, and simultaneous binding experiments showed that the ROQ and ZnF domains engage natural targets concurrently, establishing that Roquin integrates RNA shape and sequence through tandem domains.

    Evidence NMR structure, RBNS-NMR pipeline, simultaneous dual-domain binding on natural target RNAs

    PMID:38953172

    Open questions at the time
    • Whether ZnF binding is required for in vivo target selection genome-wide not tested
    • Structural model of full-length Roquin on a natural 3′ UTR not available
  17. 2025 High

    Single-molecule force spectroscopy showed that the ROQ domain A-site stabilizes while the B-site destabilizes target RNA structure, revealing that the two binding sites have opposing mechanical effects that together encode target specificity.

    Evidence SMFS with integrated NMR and microfluidics on CDE/ADE RNA elements

    PMID:40203046

    Open questions at the time
    • Whether opposing A/B-site effects operate on all target classes not tested
    • How these mechanical effects translate into differential decay kinetics in cells unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full substrate range of Roquin's RING-domain E3 ligase activity, the structural basis of the Roquin–Regnase-1 complex, how Roquin's RNA-decay and ubiquitin-ligase functions are coordinated on the same protein, and whether Roquin plays roles in non-immune tissues beyond bone metabolism.
  • No structure of the full-length Roquin–Regnase-1 complex
  • Complete E3 ligase substrate repertoire undefined
  • Coordination between RNA-decay and ubiquitin-ligase activities unknown
  • Non-immune physiological roles largely unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 11 GO:0140098 catalytic activity, acting on RNA 4 GO:0016874 ligase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0031410 cytoplasmic vesicle 6 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 1
Partners
AGO2CNOT9GPX4MALT1NUFIP2PRKAA1RC3H2ZC3H12A
Complex memberships
CCR4-NOT deadenylase complex (recruited effector)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Roquin (RC3H1) limits ICOS expression by promoting degradation of ICOS mRNA; a conserved 47-bp segment in the ICOS 3' UTR is essential for Roquin-mediated regulation, and the M199R mutation in the ROQ domain abolishes this activity in vivo. Genetic mouse model (sanroque M199R mutation), mRNA decay assays, 3' UTR functional analysis Nature High 18172933
2010 Roquin localizes to processing (P) bodies and directly binds ICOS mRNA via its 3' UTR; repression of ICOS requires the RNA helicase Rck and the decapping enhancer Edc4, and depends on P-body localization sequences in Roquin, but is independent of microRNAs or RISC. Co-immunoprecipitation, fluorescence microscopy (P-body localization), RNA binding assays, microRNA-independence demonstrated by Ago2/RISC decoupling Nature immunology High 20639877
2010 The ROQ domain of Roquin is necessary and sufficient for localization to stress granules and for triggering ICOS mRNA decay; gel-shift, SPR and footprinting show the ROQ domain binds RNA from the ICOS 3' UTR adjacent to the miR-101 complementarity site. Fluorescence microscopy, gel-shift, SPR, RNA footprinting, domain deletion analysis The FEBS journal High 20412057
2013 Roquin recognizes a constitutive decay element (CDE) stem-loop in the TNF-α 3' UTR and promotes mRNA degradation by recruiting the Ccr4-Caf1-Not deadenylase complex; CDE motifs are conserved in >50 vertebrate mRNAs encoding regulators of development and inflammation. RNA-protein binding assays, mRNA decay assays in macrophages, transcriptome-wide target identification, deadenylase complex recruitment assay Cell High 23663784
2013 Roquin-1 and Roquin-2 redundantly repress ICOS and OX40 costimulatory receptor mRNAs in T cells; the RING domain of Roquin-1 is required for stress granule localization, and its absence allows Roquin-2 to compensate, whereas the ROQ mutation disrupts mRNA regulation while preserving stress granule occupancy. Conditional gene knockout, stress granule localization (fluorescence microscopy), mRNA reporter assays, bone marrow chimeras Immunity High 23583642 23583643
2014 Crystal structure of the mouse Roquin ROQ domain in complex with CDE RNA reveals an extended winged-helix fold; the ROQ domain recognizes the RNA stem and triloop primarily through non-sequence-specific contacts, explaining broad target spectrum; cell-based assays confirm ROQ domain is sufficient for CDE-regulated mRNA decay. X-ray crystallography, NMR, binding experiments, cell-based mRNA decay assays Nature structural & molecular biology High 25026077
2014 Crystal structures of human Roquin ROQ domain reveal two distinct RNA-binding sites: the A-site binds stem-loop CDE RNA and the B-site binds double-stranded RNA at a separate interface; mutagenesis of either site disrupts Roquin-mediated degradation of HMGXB3 and IL6 mRNAs in human cells. X-ray crystallography (two crystal structures), site-directed mutagenesis, mRNA decay assays in human cells Nature structural & molecular biology High 25026078
2014 Upon TCR antigen recognition, the paracaspase MALT1 cleaves both Roquin-1 and Regnase-1; this cleavage releases cooperative post-transcriptional repression of IL-6, ICOS, c-Rel, IRF4, IκBNS, and IκBζ mRNAs, thereby promoting TH17 differentiation in a signal-strength-dependent manner. Biochemical cleavage assays, T cell genetic models, mRNA reporter assays, MALT1 activity assays Nature immunology High 25282160
2014 Crystal structure of the Roquin ROQ domain shows a winged helix-turn-helix (wHTH) motif involved in CDE stem-loop RNA binding; biochemical and mutational analyses show Roquin can bind duplex RNA and function in different oligomeric states. X-ray crystallography, biochemical binding assays, mutagenesis Nature communications High 25504471
2015 Regnase-1 and Roquin regulate an overlapping set of inflammatory mRNAs via a common stem-loop structure but act in distinct subcellular compartments: Regnase-1 degrades translationally active mRNAs at ribosomes/ER and requires UPF1 helicase activity, while Roquin acts on translationally inactive mRNAs at P-bodies/stress granules independently of UPF1. Subcellular fractionation, ribosome profiling, siRNA knockdown, mRNA decay assays, UPF1 requirement assays Cell High 26000482
2015 PAR-CLIP of human RC3H1 identifies ~3,800 mRNA targets with >16,000 binding sites; RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3' UTR; knockdown of RC3H1 increases A20 protein, thereby reducing IKK and NF-κB activities. PAR-CLIP (transcriptome-wide), domain deletion/mutagenesis, NF-κB pathway assays, siRNA knockdown Nature communications High 26170170
2015 Roquin binds Argonaute2 directly and enhances Dicer-mediated processing of pre-miR-146a; in the absence of functional Roquin, mature miR-146a accumulates due to decreased 3'-end uridylation; crystallographic studies reveal a unique HEPN domain in Roquin and define the structural basis for the sanroque mutation. Co-immunoprecipitation (Roquin-Ago2, Roquin-miR-146a), miRNA processing assays, 3'-end uridylation analysis, X-ray crystallography Nature communications High 25697406
2015 The RING domain of Roquin-1 directly antagonizes the catalytic α1 subunit of AMPK, promoting Tfh cell differentiation; T cell-specific deletion of the RING domain selectively abolishes antigen-specific Tfh responses without affecting Th1, Th2, Th17, or Treg populations. Conditional RING domain knockout mice, biochemical AMPK interaction assays, T cell subset analysis eLife High 26496200
2015 The solution structure of the CDE RNA shows a unique conformation that explains sequence-dependent recognition by Roquin; a CDE mutant with impaired Roquin binding adopts a distinct structure in both the loop and stem, revealing that Roquin recognizes CDE stem-loops in a sequence-specific manner through shape recognition. NMR solution structure determination of free and mutant CDE RNA Structure High 26165594
2015 Crystal structure of human Roquin-2 ROQ domain shows a winged-helix fold with a flexible wing acting as a lid for CDE stem-loop RNA binding; CDE recognition is primarily through phosphate backbone and triloop contacts, with conserved features between Roquin-1 and Roquin-2 explaining functional redundancy. X-ray crystallography (apo and RNA-bound forms) Acta crystallographica. Section F High 26249698
2016 Roquin-1 recognizes a novel U-rich hexaloop alternative decay element (ADE) in the Ox40 3' UTR via its ROQ domain; crystal structures and NMR data show ADE and CDE hexaloop motifs are bound with identical binding modes; ADE-like and CDE-like motifs cooperate in Ox40 repression in cells. SELEX, X-ray crystallography, NMR, cell-based repression assays Nature communications High 27010430
2017 Roquin inhibits the PI3K-mTOR signaling pathway by upregulating PTEN through competition with miR-17~92 binding to the Pten 3' UTR, and by downregulating Foxo1-specific E3 ubiquitin ligase Itch; loss of Roquin enhances Akt-mTOR signaling and PI3K inhibition corrects enhanced Tfh/Th17 differentiation phenotypes. Conditional T cell-specific and Treg-specific knockout, miR-17~92 binding competition assays, PI3K/mTOR inhibitor rescue experiments Immunity High 29246441
2017 Drosophila Roquin and human Roquin-2 recruit the CCR4-NOT deadenylase complex through C-terminal regions containing a CAF40-binding motif (CBM); crystal structure of Dm Roquin CBM bound to CAF40 shows CBM adopts an α-helical conformation binding a conserved CAF40 surface. X-ray crystallography (CBM-CAF40 complex), Co-immunoprecipitation, binding assays Nature communications High 28165457
2018 Roquin interacts not only with stem-loop structures but also with a linear sequence element present in ~half of its targets; multiple stem-loops in the Nfkbid 3' UTR cooperate for robust repression requiring binding of multiple Roquin proteins; repression involves both deadenylation/decapping and translational inhibition depending on the number of binding sites. iCLIP, reporter assays, polysome profiling, decapping/deadenylation mutant rescue, PAR-CLIP Nature communications High 30232334
2018 NUFIP2 directly and with high affinity binds Roquin-1 and -2, is stabilized by this interaction, and acts as a cofactor for Roquin-induced mRNA decay; NUFIP2 cooperates with Roquin to bind tandem non-canonical stem-loops in the ICOS and Ox40 3' UTRs required for post-transcriptional repression. siRNA screen (~1500 genes), Co-IP, affinity binding assays, cooperative RNA-binding experiments, reporter assays Nature communications High 29352114
2019 A human homozygous nonsense R688* RC3H1 mutation causes hyperinflammation; R688* Roquin-1 fails to localize to P-bodies and fails to interact with the CCR4-NOT deadenylation complex, impairing mRNA decay of immune targets including ICOS, OX40, and TNF. Patient genetic analysis, P-body localization assay, CCR4-NOT co-immunoprecipitation, mRNA decay assays Nature communications High 31636267
2019 HCMV actively induces Roquin expression; Roquin binds IRF1 mRNA via CLIP and reduces IRF1 protein expression, thereby suppressing a broad antiviral gene expression program and enabling viral replication. CLIP-seq, loss-of-function screening, transcriptome profiling, siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 31451648
2020 Roquin recognizes AU-rich elements (AREs) folded into CDE-like structures in a shape-specific manner via the ROQ domain; the same ARE sequences in the UCP3 3' UTR are also bound by AUF1 in their linear form, revealing context-dependent dual recognition of the same sequence. NMR spectroscopy (free and protein-bound RNA structures), SHAPE-seq, in-line probing, protein binding assays Nucleic acids research High 32491174
2021 Roquin-1 physically interacts with Regnase-1; the sanroque residue M199 is part of the Roquin-1 interaction surface for Regnase-1; mutations disrupting this interaction induce Tfh cells, germinal center B cells, and autoantibody formation, establishing direct physical cooperation as mechanistically required. Co-immunoprecipitation, interaction surface mapping, conditional KO mice, autoimmune phenotyping Nature immunology High 34811541
2021 Roquin (RC3H1) and its paralog are major mediators of iron-regulated transferrin receptor-1 (TfR1) mRNA degradation; Roquin destabilizes TfR1 mRNA through three hairpin loops in the TfR1 3' UTR that are essential for iron-regulated instability; this activity is translation-independent. Gene knockout (HAP1, HUVEC, L-M, MEF cells), siRNA knockdown, 3' UTR mutational analysis, mRNA decay assays iScience High 33898949
2021 RC3H1 deficiency in osteoclasts post-transcriptionally derepresses transferrin receptor 1 (Tfr1) mRNA, increasing iron uptake and mitochondrial respiration, thereby promoting osteoclast activation and bone loss; Tfr1 inhibition rescues the Rc3h1-deficient osteoclast phenotype. Conditional osteoclast-specific knockout mice, bone mass measurement, mitochondrial function assays, Tfr1 inhibition rescue Theranostics High 39659568
2022 NMR analysis of the complete Ox40 3' UTR reveals two decay elements (CDE and ADE) that are bound by Roquin in a 2:1 stoichiometry via the bimodal ROQ domain; differential binding is observed depending on structural embedment of decay elements within the full UTR context. NMR spectroscopy, SAXS, In-line probing, SHAPE-seq on complete 3' UTR Nucleic acids research High 35357505
2023 MALT1 cleavage of Roquin-1 at a specific site (rendering it insensitive to cleavage via Mins mutation) is the primary mechanism by which TCR signaling inactivates Roquin; graded TCR signal strength leads to proportionally more Roquin cleavage and differential derepression of target mRNAs, with high-affinity targets (like IκBNS) requiring stronger TCR signals for derepression; Mins mice are protected from EAE. Knock-in mice with cleavage-resistant Roquin-1 (Rc3h1Mins/Mins), genetic epistasis with constitutively active MALT1 (TBM), EAE model, Th17 differentiation assays Proceedings of the National Academy of Sciences of the United States of America High 37988467
2024 MALT1 inhibition upregulates RC3H1 (Roquin-1), which functions as an E3 ubiquitin ligase promoting ubiquitination-mediated degradation of GPX4; pharmacological MALT1 targeting thus triggers ferroptosis in liver cancer cells through the MALT1-RC3H1-GPX4 axis. FACS-based genome-wide CRISPR screen, rescue assays, ubiquitination assays, ferroptosis readouts Proceedings of the National Academy of Sciences of the United States of America High 39739814
2024 NMR solution structure of the Roquin-1 CCCH-type zinc finger (ZnF) shows it recognizes AU-rich RNA sequences; the ZnF and ROQ domain simultaneously bind natural Roquin target transcripts, suggesting Roquin integrates RNA shape (via ROQ) and sequence features (via ZnF) through their tandem arrangement. NMR structure determination, RBNS-NMR pipeline for RNA motif preference, simultaneous binding experiments with natural targets Nucleic acids research High 38953172
2025 Single-molecule force spectroscopy combined with NMR reveals the two RNA-binding sites of Roquin's ROQ domain have opposing effects on target RNA stability: the A-site strongly stabilizes the folded CDE/ADE apical stem-loop, while the B-site destabilizes the central stem of the ADE through single-strand RNA binding, suggesting RNA motif nature and A/B-site cooperation encode target specificity. Single-molecule force spectroscopy (SMFS), NMR spectroscopy, integrated microfluidics for binding kinetics Proceedings of the National Academy of Sciences of the United States of America High 40203046
2021 MNSFβ physically binds RC3H1 (Roquin-1) as shown by co-immunoprecipitation; MNSFβ promotes TNFα expression by interacting with RC3H1 and increasing RC3H1 localization to stress granules, reducing RC3H1's inhibitory effect on TNFα mRNA. Co-immunoprecipitation, stress granule localization assay, siRNA knockdown, TNFα measurement Frontiers in immunology Medium 34589082
2024 MNSFβ binds RC3H1 via its 81-326 aa region interacting with MNSFβ 101-133 aa region; MNSFβ promotes stress granule formation and RC3H1 recruitment to stress granules by interacting with RC3H1 and FMR1, sequestering RC3H1 away from TNFα mRNA and thus increasing TNFα expression. Co-immunoprecipitation, domain mapping, stress granule localization assay, peptide interference experiment, mRNA stability assay International immunopharmacology Medium 39260307
2009 Roquin acts as an E3 ubiquitin ligase; mutation of Roquin causes ICOS-dependent gain of function where CD28-mediated immune responses (Tfh cell generation, germinal center formation, T helper cell responses) become dependent on ICOS instead, demonstrating that Roquin-mediated ICOS restriction is critical for maintaining functional compartmentalization of costimulatory signals. Genetic mouse model (sanroque), immune cell subset analysis, infection challenge experiments Immunity Medium 19217324
2025 Comprehensive sRBNS (structured RNA Bind-n-Seq) mapping defines Roquin ROQ domain binding preferences at nucleotide resolution: clear preference for specific loop sizes; extended consensus motifs for CDEs and ADEs identified; new target mRNAs predicted and verified in cells. sRBNS (high-throughput structured RNA library screen), affinity measurements, cell-based reporter assays Angewandte Chemie Medium 39344866

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 352 18172933
2015 Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms. Cell 318 26000482
2013 Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell 263 23663784
2014 Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. Nature immunology 239 25282160
2013 Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity 171 23583643
2010 Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nature immunology 158 20639877
2013 Roquin-2 shares functions with its paralog Roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation. Immunity 122 23583642
2009 Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 119 19217324
2017 Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. Immunity 114 29246441
2017 Metformin Suppresses Systemic Autoimmunity in Roquin Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3. Journal of immunology (Baltimore, Md. : 1950) 112 28242651
2015 RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway. Nature communications 96 26170170
2011 Loss of Roquin induces early death and immune deregulation but not autoimmunity. The Journal of experimental medicine 89 21844204
2014 Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation. Nature structural & molecular biology 78 25026077
2017 A CAF40-binding motif facilitates recruitment of the CCR4-NOT complex to mRNAs targeted by Drosophila Roquin. Nature communications 73 28165457
2014 The ROQ domain of Roquin recognizes mRNA constitutive-decay element and double-stranded RNA. Nature structural & molecular biology 71 25026078
2010 The ROQUIN family of proteins localizes to stress granules via the ROQ domain and binds target mRNAs. The FEBS journal 71 20412057
2023 Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells. Proceedings of the National Academy of Sciences of the United States of America 66 36920923
2015 Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. Nature communications 64 25697406
2014 Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses. Science signaling 59 24448648
2015 Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation. eLife 53 26496200
2021 Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses. Nature immunology 50 34811541
2018 Roquin targets mRNAs in a 3'-UTR-specific manner by different modes of regulation. Nature communications 50 30232334
2019 Inhibition of IL-17 ameliorates systemic lupus erythematosus in Roquinsan/san mice through regulating the balance of TFH cells, GC B cells, Treg and Breg. Scientific reports 47 30914691
2019 A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nature communications 47 31636267
2016 Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40. Nature communications 47 27010430
2017 Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis. Journal of immunology (Baltimore, Md. : 1950) 43 29127149
2021 Genome-wide fitness gene identification reveals Roquin as a potent suppressor of CD8 T cell expansion and anti-tumor immunity. Cell reports 40 34879274
2013 Molecular control of Tfh-cell differentiation by Roquin family proteins. Immunological reviews 40 23550652
2021 Defining the RBPome of primary T helper cells to elucidate higher-order Roquin-mediated mRNA regulation. Nature communications 33 34471108
2018 Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA. Nature communications 33 29352114
2014 Roquin binding to target mRNAs involves a winged helix-turn-helix motif. Nature communications 32 25504471
2016 ROQUIN signalling pathways in innate and adaptive immunity. European journal of immunology 29 27060455
2020 Roquin-1 Regulates Macrophage Immune Response and Participates in Hepatic Ischemia-Reperfusion Injury. Journal of immunology (Baltimore, Md. : 1950) 22 31996460
2020 Structural basis for the recognition of transiently structured AU-rich elements by Roquin. Nucleic acids research 21 32491174
2016 RNA recognition by Roquin in posttranscriptional gene regulation. Wiley interdisciplinary reviews. RNA 21 26844532
2015 Roquin--a multifunctional regulator of immune homeostasis. Genes and immunity 21 26673963
2015 Structure of human Roquin-2 and its complex with constitutive-decay element RNA. Acta crystallographica. Section F, Structural biology communications 20 26249698
2013 Small intestine inflammation in Roquin-mutant and Roquin-deficient mice. PloS one 20 23451046
2018 Identification of new high affinity targets for Roquin based on structural conservation. Nucleic acids research 19 30295819
2012 Enforced expression of roquin protein in T cells exacerbates the incidence and severity of experimental arthritis. The Journal of biological chemistry 18 23066015
2022 NMR-derived secondary structure of the full-length Ox40 mRNA 3'UTR and its multivalent binding to the immunoregulatory RBP Roquin. Nucleic acids research 16 35357505
2021 Roquin is a major mediator of iron-regulated changes to transferrin receptor-1 mRNA stability. iScience 16 33898949
2019 Human cytomegalovirus induces and exploits Roquin to counteract the IRF1-mediated antiviral state. Proceedings of the National Academy of Sciences of the United States of America 16 31451648
2024 Deciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability. Proceedings of the National Academy of Sciences of the United States of America 13 39739814
2013 ROQUIN/RC3H1 alterations are not found in angioimmunoblastic T-cell lymphoma. PloS one 13 23825522
2022 Dynamic Regulation of the Nexus Between Stress Granules, Roquin, and Regnase-1 Underlies the Molecular Pathogenesis of Warfare Vesicants. Frontiers in immunology 12 35082795
2021 MNSFβ Regulates TNFα Production by Interacting with RC3H1 in Human Macrophages, and Dysfunction of MNSFβ in Decidual Macrophages Is Associated With Recurrent Pregnancy Loss. Frontiers in immunology 12 34589082
2017 Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets. Journal of immunology (Baltimore, Md. : 1950) 12 28188245
2020 MAP7 interacts with RC3H1 and cooperatively regulate cell-cycle progression of cervical cancer cells via activating the NF-κB signaling. Biochemical and biophysical research communications 11 32446391
2015 A Distinct, Sequence-Induced Conformation Is Required for Recognition of the Constitutive Decay Element RNA by Roquin. Structure (London, England : 1993) 11 26165594
2011 The role of Roquin overexpression in the modulation of signaling during in vitro and ex vivo T-cell activation. Biochemical and biophysical research communications 11 22155229
2024 Structure and RNA-binding of the helically extended Roquin CCCH-type zinc finger. Nucleic acids research 10 38953172
2023 Roquin-dependent gene regulation in immune-mediated diseases and future therapies. International immunology 10 36525589
2023 Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity. Proceedings of the National Academy of Sciences of the United States of America 9 37988467
2022 Analysis of ROQUIN, Tristetraprolin (TTP), and BDNF/miR-16/TTP regulatory axis in late onset Alzheimer's disease. Frontiers in aging neuroscience 9 36016853
2014 A role for IL-10 in the transcriptional regulation of Roquin-1. Gene 9 25062971
2022 Cooperation of RNA-Binding Proteins - a Focus on Roquin Function in T Cells. Frontiers in immunology 8 35251035
2022 miR-150 promotes progressive T cell differentiation via inhibiting FOXP1 and RC3H1. Human immunology 8 35999072
2023 Roquin-1 resolves sepsis-associated acute liver injury by regulating inflammatory profiles via miRNA cargo in extracellular vesicles. iScience 6 37554446
2014 Hematopoietic not systemic impairment of Roquin expression accounts for intestinal inflammation in Roquin-deficient mice. Scientific reports 6 24815331
2024 MNSFβ promotes LPS-induced TNFα expression by increasing the localization of RC3H1 to stress granules, and the interfering peptide HEPN2 reduces TNFα production by disrupting the MNSFβ-RC3H1 interaction in macrophages. International immunopharmacology 5 39260307
2024 Roquin-2 promotes oxidative stress-induced cell death by ubiquitination-dependent degradation of TAK1. Free radical biology & medicine 4 38729452
2024 Rc3h1 negatively regulates osteoclastogenesis by limiting energy metabolism. Theranostics 4 39659568
2019 Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nature communications 4 31745085
2014 Over-expression of Roquin aggravates T cell mediated hepatitis in transgenic mice using T cell specific promoter. Biochemical and biophysical research communications 4 25201726
2025 Roquin-1 interaction with Regnase-1 inhibits the progression of rheumatoid arthritis via suppressing FGF2 expression and NF-κB pathway. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 3 40097661
2025 Enhanced Therapeutic Effect of IL-10-ADSCs on Rabbit Autoimmune Dacryoadenitis By Suppressing T Follicular Helper Cell Responses Via miR-142-5p/RC3H1 Axis. Investigative ophthalmology & visual science 3 40261659
2022 The silencing of ets-4 mRNA relies on the functional cooperation between REGE-1/Regnase-1 and RLE-1/Roquin-1. Nucleic acids research 3 35819231
2020 RNA-binding protein Roquin negatively regulates STING-dependent innate immune response in Drosophila. Yi chuan = Hereditas 3 33509784
2013 Roquin paralogs add a new dimension to ICOS regulation. Immunity 3 23601678
2024 Comprehensive Profiling of Roquin Binding Preferences for RNA Stem-Loops. Angewandte Chemie (International ed. in English) 2 39344866
2025 Evolution of the RNA alternative decay cis element into a high-affinity target for the immunomodulatory protein Roquin. RNA biology 1 39801464
2017 Modulation of Roquin Function in Myeloid Cells Reduces Mycobacterium tuberculosis-Induced Inflammation. Journal of immunology (Baltimore, Md. : 1950) 1 28747346
2026 miR-3613-3p Is a New Diagnostic Indicator of Acute Coronary Syndrome (ACS) That Reduces Endothelial Damage by Targeting Ring Finger and CCCH-Type Domains 1 (RC3H1). Journal of biochemical and molecular toxicology 0 41943150
2025 Roquin exhibits opposing effects on RNA stem-loop stability through its two ROQ domain binding sites. Proceedings of the National Academy of Sciences of the United States of America 0 40203046
2025 Identification of RC3H1 as antiviral host factor binding to the non-structural protein 1 of Influenza A virus via a 3-stage computational pipeline and cell-based analysis. Virology journal 0 40287742
2025 Autosomal-dominant Roquin-1 immunodeficiency and hyperinflammation. The Journal of allergy and clinical immunology 0 40769319
2025 Targeting RNA-Binding proteins Roquin-1 and Regnase-1 could enhance CAR-iPSC-derived macrophage immunotherapy for solid tumors: a perspective and challenges. RNA biology 0 41147512
2025 Roquin Modulates Cardiac Post-Infarct Remodeling via microRNA Stability Control. Cells 0 41294801
2025 Serous Cavity Mast Cells Depend on the ROQUIN Paralogs. European journal of immunology 0 41416953