Affinage

Showing RC3H1 — ROQUIN is a alias.

RC3H1

Roquin-1 · UniProt Q5TC82

Length
1133 aa
Mass
125.7 kDa
Annotated
2026-06-10
80 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RC3H1 (Roquin-1) is an RNA-binding post-transcriptional repressor that silences inflammatory and co-stimulatory mRNAs by recognizing structured decay elements in their 3' UTRs and targeting them for degradation (PMID:18172933, PMID:23663784). Its central ROQ domain adopts an extended winged-helix fold that recognizes stem-loop constitutive decay elements (CDEs) largely through shape-specific backbone contacts to the stem and triloop (PMID:25026077, PMID:25504471), and contains two distinct RNA-binding surfaces — an A site that engages folded stem-loops and a B site that binds duplex/single-stranded RNA — both of which are required for efficient target decay (PMID:25026078, PMID:40203046). Beyond the canonical CDE triloop, the ROQ domain also recognizes U-rich hexaloop alternative decay elements (ADEs) and CDE-folded AU-rich elements with the same binding mode, while the flanking CCCH zinc finger reads AU-rich sequence so that shape and sequence recognition are integrated across tandem domains; multiple decay elements within a single 3' UTR are engaged cooperatively (PMID:27010430, PMID:32491174, PMID:38953172, PMID:35357505). Roquin drives decay by recruiting the CCR4-NOT deadenylase complex via a CAF40-binding motif and by acting through decapping factors (Rck/Edc4) at P-bodies and stress granules, where it controls translationally inactive mRNAs in cooperation with the ribosome-associated endonuclease Regnase-1 that handles translationally active transcripts (PMID:20639877, PMID:23663784, PMID:28165457, PMID:26000482, PMID:34811541). Validated targets include ICOS, Ox40, TNF, IL-6, A20, IRF1 and transferrin receptor 1 (TfR1) mRNAs, linking Roquin to control of follicular helper and effector T-cell responses, NF-κB signaling, antiviral IRF1 responses, and iron homeostasis (PMID:18172933, PMID:23583643, PMID:23583642, PMID:26170170, PMID:31451648, PMID:33898949, PMID:39659568). Roquin activity is set by T-cell receptor signal strength: the paracaspase MALT1 cleaves Roquin-1 in a graded, signal-strength-dependent manner to derepress target mRNAs and license Th17 differentiation (PMID:25282160, PMID:37988467). Loss-of-function and missense ROQ-domain mutations in humans cause immune disease — a homozygous R688* nonsense allele produces HLH-like hyperinflammation through failed P-body localization and CCR4-NOT recruitment, and a heterozygous F225S ROQ variant causes autosomal-dominant primary immunodeficiency through loss of mRNA repression (PMID:31636267, PMID:40769319). Separately, Roquin functions as an E3 ubiquitin ligase promoting GPX4 ubiquitination and ferroptosis (PMID:39739814).

Mechanistic history

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

    Established that Roquin is a physiological repressor of an immune mRNA, defining its core function before any molecular mechanism was known.

    Evidence sanroque M199R point-mutant mouse, ICOS 3' UTR reporter and mRNA stability assays

    PMID:18172933

    Open questions at the time
    • Did not identify the RNA element recognized or the decay machinery engaged
    • Mechanism of the M199R defect unresolved at the structural level
  2. 2010 High

    Localized Roquin function to RNA-decay foci and identified decapping machinery, showing it acts directly on mRNA independent of the RISC pathway.

    Evidence P-body/stress-granule fluorescence microscopy, Rck/Edc4 Co-IP, RNA-binding and deletion-mutant analysis in helper T cells

    PMID:20412057 PMID:20639877

    Open questions at the time
    • The precise RNA structural motif recognized was not defined
    • Whether deadenylation precedes decapping was not established
  3. 2013 High

    Defined the constitutive decay element (CDE) stem-loop as the recognition motif and CCR4-NOT recruitment as the decay mechanism, generalizing Roquin to a regulon of inflammatory mRNAs.

    Evidence In vitro RNA binding, macrophage decay assays, CCR4-NOT Co-IP, transcriptome-wide target identification

    PMID:23663784

    Open questions at the time
    • Structural basis of CDE recognition not yet solved
    • Did not explain redundancy with the Roquin-2 paralog
  4. 2013 High

    Demonstrated functional redundancy between Roquin-1 and Roquin-2 and dissected RING-domain contribution to subcellular targeting, clarifying genetic interpretation of single-paralog studies.

    Evidence Single and double conditional T-cell knockouts, RING-domain mouse models, flow cytometry, mRNA stability assays

    PMID:23583642 PMID:23583643

    Open questions at the time
    • Molecular role of the RING domain in stress-granule localization left mechanistically open
    • Did not resolve whether RING has catalytic ligase activity in this context
  5. 2014 High

    Provided crystal structures of the ROQ domain bound to CDE RNA, revealing a winged-helix fold with two RNA-binding sites that read RNA shape rather than sequence.

    Evidence X-ray crystallography of mouse and human ROQ domains, NMR, mutagenesis, cell-based decay reporters

    PMID:25026077 PMID:25026078 PMID:25504471

    Open questions at the time
    • Did not address how full 3' UTRs with multiple elements are engaged
    • Role of the zinc finger in RNA recognition unresolved
  6. 2014 High

    Identified MALT1 cleavage of Roquin downstream of TCR signaling as the switch that derepresses targets and drives Th17 differentiation, linking Roquin to signal-dependent control.

    Evidence MALT1 cleavage assays, T-cell deletion/reconstitution, decay assays, Th17 differentiation readouts

    PMID:25282160

    Open questions at the time
    • Did not establish how cleavage extent is tuned to signal strength
    • Cooperative mechanism with Regnase-1 not fully resolved
  7. 2015 High

    Separated Roquin and Regnase-1 into distinct subcellular decay pathways acting on overlapping targets, explaining their non-redundant cooperation.

    Evidence Subcellular fractionation, ribosome profiling, UPF1 knockdown, fluorescence microscopy, decay assays

    PMID:26000482

    Open questions at the time
    • Physical basis of Roquin–Regnase-1 cooperation not yet mapped
    • How targets are partitioned between compartments unclear
  8. 2015 High

    Mapped the transcriptome-wide binding landscape and extended the binding repertoire to U-rich and linear motifs, while linking Roquin to A20/NF-κB control and miRNA biogenesis.

    Evidence PAR-CLIP, domain mutagenesis, NF-κB reporters, Ago2/miR-146a Co-IP, Dicer processing and uridylation assays, crystallography

    PMID:25697406 PMID:26170170

    Open questions at the time
    • Functional weight of linear versus structured motifs not quantified
    • Relationship between mRNA decay and miRNA-processing roles unresolved
  9. 2016 High

    Defined the alternative decay element (ADE), a U-rich hexaloop, as a second class of structured motif recognized by the same ROQ surface, broadening the structural code for target recognition.

    Evidence SELEX, X-ray crystallography, NMR, cell-based reporter assays of Ox40 elements

    PMID:27010430

    Open questions at the time
    • How CDE and ADE elements cooperate within a UTR was not structurally resolved
    • Did not address stoichiometry on full-length transcripts
  10. 2017 High

    Identified a CAF40-binding motif as the direct molecular link recruiting the CCR4-NOT complex, defining the conserved effector step of Roquin-mediated decay.

    Evidence Crystal structure of Roquin CBM–CAF40, Co-IP, pulldowns, decay reporter assays

    PMID:28165457

    Open questions at the time
    • Did not resolve coordination of deadenylation with decapping in vivo
    • Contribution of CBM versus P-body localization to net decay unclear
  11. 2018 High

    Showed that multiple Roquin molecules engage several stem-loops redundantly to enforce repression through deadenylation, decapping and translational inhibition, and identified NUFIP2 as a required cofactor.

    Evidence PAR-CLIP, polysome profiling, CRISPR 3' UTR deletions, siRNA screen, in vitro binding and reporter assays

    PMID:29352114 PMID:30232334

    Open questions at the time
    • Generality of NUFIP2 dependence across the target set not defined
    • Stoichiometry of multi-element engagement not structurally resolved
  12. 2019 High

    Connected Roquin to human disease and to antiviral and metabolic signaling, showing loss of function causes hyperinflammation and that viruses co-opt Roquin to blunt IRF1 responses.

    Evidence Patient cells with R688* (IF, CCR4-NOT Co-IP, decay assays), CLIP-seq and loss-of-function screening in HCMV infection, PI3K-mTOR rescue and reporter assays

    PMID:29246441 PMID:31451648 PMID:31636267

    Open questions at the time
    • PI3K-mTOR regulation rests on single-lab Medium evidence
    • Causality of the HCMV-Roquin axis in vivo not established
  13. 2021 High

    Mapped the physical Roquin-1–Regnase-1 interaction surface (including the sanroque residue) and extended Roquin function to iron homeostasis via TfR1 mRNA, while genome-wide screens flagged it as a dominant brake on CD8 T-cell expansion.

    Evidence Co-IP and interaction mapping, conditional triple-KO epistasis, TfR1 3' UTR hairpin mutagenesis and decay assays in multiple cell types, CRISPR screens, MNSFβ Co-IP

    PMID:33898949 PMID:34589082 PMID:34811541 PMID:34879274

    Open questions at the time
    • MNSFβ interaction and CD8 expansion roles rest on single-lab Medium evidence
    • How the same residue serves both RNA recognition and Regnase-1 binding not fully separated
  14. 2022 High

    Resolved how Roquin engages an intact 3' UTR, showing sequential bimodal engagement of decay elements with defined stoichiometry dependent on RNA structural context.

    Evidence NMR, SAXS, in-line probing and SHAPE-seq on full-length Ox40 3' UTR, binding assays

    PMID:35357505

    Open questions at the time
    • Did not link binding order to in-cell decay kinetics
    • Role of cofactors in shaping engagement not addressed
  15. 2023 High

    Demonstrated that MALT1 converts TCR signal strength into graded Roquin-1 cleavage, establishing an analog-to-threshold mechanism for selective target derepression.

    Evidence Cleavage-resistant knock-in mice, genetic epistasis with constitutively active MALT1, EAE and Th17 assays, cleavage western blots

    PMID:37988467

    Open questions at the time
    • Affinity hierarchy that sets target thresholds not biochemically mapped for all targets
    • Whether Regnase-1 cleavage is similarly graded not addressed here
  16. 2024 High

    Defined the zinc-finger contribution to RNA recognition and revealed a distinct E3 ligase function promoting GPX4 degradation and ferroptosis, broadening Roquin beyond mRNA decay.

    Evidence NMR solution structure of the CCCH ZnF with RBNS-NMR binding, CRISPR screen with ubiquitination and rescue assays, osteoclast conditional KO with TfR1 rescue, MNSFβ stress-granule imaging

    PMID:38953172 PMID:39260307 PMID:39659568 PMID:39739814

    Open questions at the time
    • E3 ligase activity toward GPX4 rests on single-lab Medium evidence
    • Relationship between RNA-decay and ubiquitin-ligase functions not reconciled
  17. 2025 High

    Provided biophysical insight into how the two ROQ RNA-binding sites exert opposing structural effects on a target stem-loop, and added a second human disease allele confirming ROQ-domain integrity as essential for repression.

    Evidence Single-molecule force spectroscopy and NMR on ADE stem-loops; whole-exome sequencing and F225S patient-cell mRNA stability assays

    PMID:40203046 PMID:40769319

    Open questions at the time
    • F225S mechanism rests on single-variant transfection (Medium)
    • How A-/B-site cooperation selects targets in cells not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Roquin's mRNA-decay activity and its E3 ubiquitin-ligase/GPX4-ferroptosis activity are coordinated within a cell, and whether they share regulatory inputs, remains unresolved.
  • No structural or genetic dissection separating the two activities
  • Substrate scope of the E3 ligase function beyond GPX4 unknown
  • Whether MALT1 cleavage regulates the ligase activity untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 9 GO:0140098 catalytic activity, acting on RNA 4 GO:0060090 molecular adaptor activity 2 GO:0016874 ligase activity 1
Localization
GO:0031410 cytoplasmic vesicle 6 GO:0005829 cytosol 3
Pathway
R-HSA-168256 Immune System 6 R-HSA-8953854 Metabolism of RNA 5 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 1
Partners
AGO2CAF40CNOT1/CCR4-NOTGPX4MALT1MNSFΒNUFIP2REGNASE-1 (ZC3H12A)
Complex memberships
P-bodystress granule

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Roquin (RC3H1) promotes degradation of ICOS mRNA via a conserved 47-bp segment in the ICOS 3' UTR; the M199R sanroque mutation in the ROQ domain abolishes this repression, leading to increased ICOS expression on T cells and lupus-like autoimmunity. Genetic mouse model (sanroque M199R point mutation), mRNA stability assays, 3' UTR reporter assays Nature High 18172933
2010 Roquin localizes to processing (P) bodies in helper T cells and represses ICOS expression by directly binding the ICOS mRNA 3' UTR (independent of microRNAs/RISC); repression requires the RNA helicase Rck and the decapping enhancer Edc4, and depends on sequences conferring P-body localization. Fluorescence microscopy (P-body localization), co-immunoprecipitation (Rck, Edc4 interactions), RNA binding assays, dominant-negative and deletion mutant analysis 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; Roquin and its orthologs (Drosophila, C. elegans) all concentrate in stress granules via the ROQ domain. Fluorescence microscopy, deletion mutant analysis, gel-shift/SPR/footprinting RNA-binding assays The FEBS journal High 20412057
2013 Roquin recognizes a conserved stem-loop motif (constitutive decay element, CDE) in the 3' UTR of TNF-α mRNA and initiates its degradation by recruiting the Ccr4-Caf1-Not deadenylase complex; CDE sequences are present in >50 vertebrate mRNAs encoding inflammatory and developmental regulators. In vitro RNA-binding assays, mRNA stability assays in macrophages, co-immunoprecipitation of Ccr4-Caf1-Not, transcriptome-wide target identification (RNA-seq) Cell High 23663784
2013 Roquin-1 and Roquin-2 redundantly repress ICOS and Ox40 costimulatory receptor mRNAs in T cells; combined loss of both paralogs (but not either alone) causes accumulation of follicular helper T cells and effector T cells. Conditional gene knockout (T-cell-specific deletion), flow cytometry, mRNA stability assays Immunity High 23583642 23583643
2013 The RING domain of Roquin-1 is required for its localization to stress granules; RING-deficient Roquin-1 fails to localize to stress granules and permits Roquin-2 to compensate for ICOS and Tfh repression, whereas the ROQ (sanroque) mutant retains stress granule localization. Conditional knock-in/knockout mouse models, fluorescence microscopy, flow cytometry Immunity Medium 23583642
2014 Crystal structure of the mouse Roquin ROQ domain in complex with a CDE RNA stem-loop reveals that the ROQ domain adopts an extended winged-helix (WH) fold and recognizes mainly via non-sequence-specific contacts to the RNA stem and triloop. X-ray crystallography, NMR, binding assays, cell-based reporter assays Nature structural & molecular biology High 25026077
2014 Crystal structures of human Roquin ROQ domain reveal two separate RNA-binding sites: the A site binds stem-loop RNA (CDE) and the B site binds double-stranded RNA; mutagenesis of either site impairs Roquin-mediated degradation of HMGXB3 and IL6 mRNAs in human cells. X-ray crystallography, 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, inactivating their cooperative post-transcriptional repression of target mRNAs (IL-6, ICOS, c-Rel, IRF4, IκBNS, IκBζ) and thereby promoting Th17 differentiation; this derepression requires RNA binding by roquin and nuclease activity of regnase-1. MALT1 cleavage assays, T cell-specific deletion/reconstitution, mRNA decay assays, Th17 differentiation assays Nature immunology High 25282160
2014 Crystal structure of the Roquin ROQ domain shows a winged helix-turn-helix motif responsible for CDE stem-loop binding; Roquin proteins can also 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 mRNAs via a common stem-loop structure but operate in distinct subcellular compartments: Regnase-1 degrades translationally active mRNAs at the ribosome/ER (requiring UPF1 helicase), whereas Roquin controls translationally inactive mRNAs at P-bodies/stress granules (independent of UPF1). Subcellular fractionation, ribosome profiling, mRNA decay assays, UPF1 knockdown, fluorescence microscopy Cell High 26000482
2015 RC3H1/Roquin binds ~3,800 mRNA targets via CDE motifs and a novel U-rich sequence embedded in hairpins (identified by PAR-CLIP); RC3H1 uses its ROQ and Zn-finger domains to contact a binding site in the A20 3' UTR, leading to A20 mRNA decay; RC3H1 knockdown increases A20 protein expression, thereby attenuating IKK and NF-κB activity. PAR-CLIP (transcriptome-wide binding), siRNA knockdown, western blotting, NF-κB reporter assays, domain mutagenesis Nature communications High 26170170
2015 Roquin directly binds Argonaute2 (Ago2) and miR-146a; Roquin enhances Dicer-mediated processing of pre-miR-146a; in the absence of functional Roquin, mature miR-146a is stabilized due to decreased 3'-end uridylation. Crystallography reveals a unique HEPN domain in Roquin and the structural basis of the sanroque mutation. Co-immunoprecipitation (Ago2, miR-146a), Dicer processing assays, miRNA uridylation assays, X-ray crystallography Nature communications High 25697406
2015 Crystal structure of the human Roquin-2 ROQ domain bound to CDE RNA shows a winged-helix fold with a flexible wing region acting as a lid for RNA binding; CDE stem-loop is recognized mainly via backbone contacts, consistent with Roquin-1 binding mode. X-ray crystallography (ligand-free and RNA-bound forms) Acta crystallographica. Section F, Structural biology communications High 26249698
2015 The ROQUIN RING domain directly antagonizes the catalytic α1 subunit of AMPK, promoting Tfh cell differentiation; T cell-specific deletion of the RING domain selectively abolishes Tfh responses without affecting Th1, Th2, Th17, or Treg populations. Conditional RING domain deletion in T cells, genetic interaction/rescue experiments, AMPK activity assays eLife Medium 26496200
2016 Roquin recognizes a novel U-rich hexaloop motif (alternative decay element, ADE) in addition to the triloop CDE; crystal structures and NMR show the ROQ domain binds ADE hexaloops from SELEX-derived sequences and from the Ox40 3' UTR with identical binding modes; ADE-like and CDE-like motifs cooperate in Ox40 repression. SELEX, X-ray crystallography, NMR, cell-based reporter assays Nature communications High 27010430
2017 Drosophila Roquin (and human Roquin-2) recruits the CCR4-NOT deadenylase complex via a CAF40-binding motif (CBM) in their C-terminal regions; crystal structure of Dm Roquin CBM bound to CAF40 shows the CBM adopts an α-helical conformation binding a conserved CAF40 surface. X-ray crystallography, co-immunoprecipitation, pulldown assays, mRNA decay reporter assays Nature communications High 28165457
2017 Roquin inhibits the PI3K-mTOR signaling pathway by upregulating PTEN (by interfering with miR-17~92 binding to the PTEN 3' UTR) and by downregulating the Foxo1-specific E3 ubiquitin ligase Itch; loss of Roquin in T cells enhances Akt-mTOR signaling and protein synthesis. Conditional Roquin knockout in Treg cells, PI3K/mTOR inhibitor rescue experiments, luciferase 3' UTR reporter assays, western blotting Immunity Medium 29246441
2018 Roquin not only interacts with stem-loop structures but also with a linear sequence element in ~half of its target mRNAs; multiple Roquin proteins bound to several stem-loops in the Nfkbid 3' UTR exert full repression redundantly via deadenylation, decapping, and translational inhibition. PAR-CLIP, luciferase reporter assays with stem-loop mutations, polysome profiling, CRISPR-mediated deletion of 3' UTR elements Nature communications High 30232334
2018 NUFIP2 directly binds Roquin with high affinity and stabilizes NUFIP2 in cells; NUFIP2 acts as a cofactor required for Roquin-mediated repression of ICOS mRNA, cooperatively binding with Roquin to non-canonical tandem stem-loops in the ICOS 3' UTR. siRNA screen (~1500 genes), co-immunoprecipitation, in vitro binding assays, reporter assays, electrophoretic mobility shift assays Nature communications High 29352114
2019 A human homozygous nonsense R688* RC3H1 mutation causes Roquin-1 loss that leads to hyperinflammation (HLH-like); mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impairing mRNA decay of ICOS, OX40, and TNF targets. Patient-derived cells, immunofluorescence (P-body localization), co-immunoprecipitation (CCR4-NOT), mRNA stability assays, flow cytometry Nature communications High 31636267
2019 HCMV exploits Roquin by upregulating its expression; Roquin binds directly to IRF1 mRNA (identified by CLIP-seq) and reduces IRF1 expression, thereby suppressing IRF1-dependent antiviral gene activation during HCMV infection. CLIP-seq, loss-of-function screening, transcriptome profiling, mRNA stability assays Proceedings of the National Academy of Sciences of the United States of America Medium 31451648
2020 The Roquin ROQ domain recognizes AU-rich elements (AREs) in a CDE-like stem-loop conformation, while AUF1 recognizes the same AREs in a linear form; NMR structures of CDE-like folded AREs (free and Roquin-bound) demonstrate shape-specific recognition by Roquin. NMR spectroscopy (solution structures of free and protein-bound AREs), RNA binding assays Nucleic acids research High 32491174
2021 RC3H1/Roquin is a major mediator of iron-regulated TfR1 mRNA stability; Roquin destabilizes TfR1 mRNA in a manner fully dependent on three hairpin loops in the TfR1 3' UTR; TfR1 mRNA degradation by Roquin does not require ongoing translation. Gene knockout (HAP1, HUVEC, L-M, MEF cells), siRNA knockdown, 3' UTR hairpin loop mutagenesis, mRNA stability assays iScience High 33898949
2021 Physical interaction between Roquin-1 and Regnase-1 is mediated by a defined interaction surface in Roquin-1 that includes the sanroque residue (M199); mutations disrupting this interaction cause Tfh cell accumulation, germinal center B cells, and autoantibody formation. Co-immunoprecipitation, mutagenesis (interaction surface mapping), conditional triple KO (Roquin-1/2 and Regnase-1), flow cytometry Nature immunology High 34811541
2021 Roquin is the strongest repressor of CD8 T cell expansion identified in genome-wide CRISPR screens; Roquin ablation boosts T cell proliferation by enhancing cell-cycle progression and upregulating IRF4. In vivo and in vitro CRISPR screens, KO validation, flow cytometry, gene expression analysis Cell reports Medium 34879274
2022 NMR analysis of the full-length Ox40 mRNA 3' UTR reveals that Roquin uses its extended bimodal ROQ domain to sequentially engage decay elements in a 2:1 (protein:RNA) stoichiometry; the binding of Roquin to individual decay elements depends on their structural embedment within the full 3' UTR. NMR spectroscopy, SAXS, In-line probing, SHAPE-seq, binding assays Nucleic acids research High 35357505
2023 TCR signal strength is translated by MALT1 into graded cleavage of Roquin-1; only high TCR strength enables derepression of high-affinity Roquin targets (e.g., IκBNS) and promotes Th17 differentiation; rendering Roquin-1 insensitive to MALT1 cleavage (Rc3h1Mins/Mins) prevents spontaneous T cell activation caused by constitutively active MALT1. Knock-in mice (MALT1-cleavage-resistant Roquin-1), genetic epistasis (Rc3h1Mins × Malt1TBM), EAE model, Th17 differentiation assays, western blotting for Roquin cleavage Proceedings of the National Academy of Sciences of the United States of America High 37988467
2024 RC3H1 acts as an E3 ubiquitin ligase promoting GPX4 ubiquitination-mediated degradation; MALT1 inhibition upregulates RC3H1, which then enhances GPX4 ubiquitination and degradation to induce ferroptosis in liver cancer cells. Genome-wide CRISPR screen (FACS-based), rescue assays, ubiquitination assays, western blotting Proceedings of the National Academy of Sciences of the United States of America Medium 39739814
2024 Rc3h1 post-transcriptionally represses transferrin receptor 1 (Tfr1) mRNA in osteoclasts, restricting iron absorption and mitochondrial respiration; Rc3h1-deficient osteoclasts show enhanced Tfr1 expression, increased mitochondrial respiration and osteoclast activation, and mice exhibit low bone mass. Conditional Rc3h1 knockout in osteoclasts, mRNA stability assays, iron content measurement, mitochondrial respiration assays, Tfr1 inhibitor rescue Theranostics Medium 39659568
2024 Solution NMR structure of the Roquin-1 CCCH zinc finger domain reveals it recognizes AU-rich RNA sequences; the ZnF and ROQ domains simultaneously bind a natural Roquin target transcript, suggesting Roquin integrates RNA shape (ROQ) and sequence (ZnF) features through a tandem domain mechanism. NMR spectroscopy (solution structure), RBNS-NMR pipeline for RNA binding preferences, in vitro RNA binding assays Nucleic acids research High 38953172
2021 MNSFβ binds directly to RC3H1 (demonstrated by co-immunoprecipitation), and elevated MNSFβ promotes TNFα production by interacting with RC3H1, which normally suppresses TNFα mRNA. Co-immunoprecipitation, siRNA knockdown in THP1-derived macrophages, ELISA Frontiers in immunology Medium 34589082
2024 MNSFβ promotes LPS-induced TNFα expression by facilitating stress granule formation and translocation of RC3H1 to stress granules (via interaction with RC3H1 and FMR1), thereby inactivating RC3H1-mediated TNFα mRNA degradation; the RC3H1 81-326 aa region binds MNSFβ 101-133 aa region. Co-immunoprecipitation, domain mapping, stress granule imaging, mRNA stability assays, peptide inhibitor (HEPN2) rescue experiments International immunopharmacology Medium 39260307
2025 Single-molecule force spectroscopy (SMFS) combined with NMR reveals opposing effects of the two Roquin ROQ domain RNA-binding sites on ADE stem stability: the A-site strongly stabilizes the apical ADE stem-loop, while the B-site destabilizes the ADE central stem through single-strand RNA binding, suggesting both sites jointly direct mRNA decay with context-dependent 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
2025 A heterozygous missense F225S variant in the ROQ domain of RC3H1 causes autosomal-dominant primary immunodeficiency; F225S Roquin-1 fails to repress ICOS1, IL6, and other target mRNAs (increased message stability), demonstrating that ROQ domain integrity is required for post-transcriptional repression. Whole-exome sequencing, patient primary cells, transfection of F225S variant, mRNA stability assays, flow cytometry The Journal of allergy and clinical immunology Medium 40769319

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 321 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 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) 115 28242651
2017 Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. Immunity 115 29246441
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 67 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
2018 Roquin targets mRNAs in a 3'-UTR-specific manner by different modes of regulation. Nature communications 51 30232334
2021 Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses. Nature immunology 50 34811541
2019 A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nature communications 48 31636267
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
2016 Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40. Nature communications 47 27010430
2021 Genome-wide fitness gene identification reveals Roquin as a potent suppressor of CD8 T cell expansion and anti-tumor immunity. Cell reports 43 34879274
2017 Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis. Journal of immunology (Baltimore, Md. : 1950) 43 29127149
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) 23 31996460
2015 Roquin--a multifunctional regulator of immune homeostasis. Genes and immunity 22 26673963
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
2018 Identification of new high affinity targets for Roquin based on structural conservation. Nucleic acids research 20 30295819
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
2012 Enforced expression of roquin protein in T cells exacerbates the incidence and severity of experimental arthritis. The Journal of biological chemistry 18 23066015
2021 Roquin is a major mediator of iron-regulated changes to transferrin receptor-1 mRNA stability. iScience 17 33898949
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
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
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 13 34589082
2017 Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets. Journal of immunology (Baltimore, Md. : 1950) 13 28188245
2013 ROQUIN/RC3H1 alterations are not found in angioimmunoblastic T-cell lymphoma. PloS one 13 23825522
2024 Structure and RNA-binding of the helically extended Roquin CCCH-type zinc finger. Nucleic acids research 12 38953172
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
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
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 Cooperation of RNA-Binding Proteins - a Focus on Roquin Function in T Cells. Frontiers in immunology 9 35251035
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 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 7 37554446
2014 Hematopoietic not systemic impairment of Roquin expression accounts for intestinal inflammation in Roquin-deficient mice. Scientific reports 6 24815331
2024 Roquin-2 promotes oxidative stress-induced cell death by ubiquitination-dependent degradation of TAK1. Free radical biology & medicine 5 38729452
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 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
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 1 41147512
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 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

Missed literature

Know a paper Affinage missed for RC3H1? Flag it for the maintainers and the community.

No submissions yet.