Affinage

ZC3H12A

Endoribonuclease ZC3H12A · UniProt Q5D1E8

Length
599 aa
Mass
65.7 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZC3H12A (Regnase-1/MCPIP1) is a PIN domain endoribonuclease that functions as a master post-transcriptional brake on inflammation by recognizing and cleaving stem-loop structures in the 3′ UTRs of proinflammatory mRNAs — including IL-6, IL-12, c-Rel, NFKBIZ, IL-8, C/EBPβ, and IL-17 receptor subunits — as well as viral RNAs and precursor miRNAs (PMID:22561375, PMID:26000482, PMID:22055188, PMID:23355615, PMID:27513529). Regnase-1 acts co-translationally at the ribosome/ER in a UPF1 helicase-dependent manner, where UPF1 unwinds target stem-loops to enable cleavage, and it physically cooperates with the RNA-binding protein Roquin-1 through a defined interaction surface to synergistically repress shared inflammatory transcripts (PMID:26000482, PMID:31329944, PMID:34811541). Its activity is dynamically controlled by IKK-mediated phosphorylation leading to proteasomal degradation upon TLR/IL-1R signaling, MALT1 paracaspase cleavage at R111 upon TCR stimulation, IRAK1-dependent 14-3-3 sequestration that blocks mRNA access, Act1–TBK1/IKKi phosphorylation that releases it from the ER upon IL-17 stimulation, and TUT7-mediated uridylation of its own mRNA, while Regnase-1 also auto-regulates by destabilizing its own transcript via a 3′ UTR stem-loop (PMID:22037600, PMID:23706741, PMID:34636324, PMID:31072819, PMID:34188032). Beyond mRNA decay, Regnase-1 suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops in competition with Dicer, recruits the deubiquitinase USP10 to NEMO to terminate NF-κB signaling, and regulates diverse cell fates in T cells, NK cells, ILC2s, HSPCs, and intestinal epithelium through degradation of lineage-specific transcripts such as BATF, Tcf7, Gata2, and Gata3 (PMID:22055188, PMID:24270572, PMID:31827283, PMID:30842549, PMID:32978308).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2010 Medium

    Establishing transcriptional control: identification of how ZC3H12A expression is itself induced revealed that it is an immediate-early gene driven by IL-1β through MAP kinase–Elk-1/SRF signaling at a compact promoter region.

    Evidence Promoter deletion reporters, ChIP for Elk-1/SRF, MAP kinase inhibitors in primary macrophages

    PMID:20137095

    Open questions at the time
    • Single lab; no genome-wide identification of additional transcription factors
    • Upstream chromatin context not addressed
    • Regulation by signals other than IL-1β at this promoter not tested
  2. 2011 High

    Defining the enzymatic mechanism and its regulation: three concurrent studies established that Regnase-1 is a bona fide endoribonuclease that degrades IL-6 mRNA, is regulated by IKK-mediated phosphorylation and proteasomal degradation forming a negative feedback loop, and additionally suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops.

    Evidence Phosphorylation/ubiquitination assays with genetic KO (IL-6 axis); in vitro pre-miRNA cleavage with domain mutagenesis and Dicer competition (miRNA axis); mRNA half-life measurements

    PMID:22037600 PMID:22055188

    Open questions at the time
    • Structural basis of RNA recognition not yet resolved
    • Identity of the full target mRNA repertoire unknown
    • Relative contribution of mRNA decay vs. miRNA suppression in vivo unresolved
  3. 2012 High

    Solving the atomic structure of the catalytic domain revealed a PIN-like RNase fold and identified both the catalytic acidic residues and a positively charged RNA-binding arm, providing the structural framework for understanding substrate recognition.

    Evidence 2.0 Å X-ray crystal structure with site-directed mutagenesis abolishing RNase activity

    PMID:22561375

    Open questions at the time
    • No RNA-bound co-crystal structure
    • Zinc finger and oligomerization domain structures not resolved
    • Structural basis for stem-loop selectivity unknown
  4. 2013 High

    Discovery of MALT1-mediated cleavage at R111 upon TCR stimulation established how adaptive immune activation inactivates Regnase-1, freeing T cells from its suppressive activity on c-Rel, Ox40, and Il2 mRNAs.

    Evidence In vitro MALT1 cleavage assay with site mapping, validated in conditional KO T cells

    PMID:23706741

    Open questions at the time
    • Kinetics of MALT1 cleavage relative to other regulatory inputs not defined
    • Whether MALT1 cleavage products have residual function unknown
  5. 2013 High

    Demonstration that Regnase-1 has broad-spectrum antiviral activity through direct RNase-mediated degradation of viral RNA expanded its role beyond endogenous mRNA regulation to innate antiviral defense.

    Evidence In vitro viral RNA cleavage, domain mutagenesis across multiple virus models (JEV, DENV, HIV, HCV, influenza)

    PMID:23355615 PMID:24191027 PMID:25225661

    Open questions at the time
    • In vivo antiviral efficacy not demonstrated for all viruses
    • Mechanism of viral RNA recognition specificity vs. host mRNA unclear
    • Viral countermeasures beyond KSHV not characterized
  6. 2013 High

    Identification of USP10 recruitment to NEMO for linear polyubiquitin removal revealed a non-catalytic scaffolding function of Regnase-1 in terminating NF-κB signaling, distinct from its RNase activity.

    Evidence Reciprocal co-immunoprecipitation, deubiquitination assay, siRNA knockdown, NF-κB reporter

    PMID:24270572

    Open questions at the time
    • Whether USP10 recruitment requires specific Regnase-1 domains beyond those tested
    • Relevance across cell types beyond genotoxic stress context
    • Relationship to RNase-dependent NF-κB regulation unclear
  7. 2015 High

    Spatiotemporal dissection established that Regnase-1 and Roquin regulate the same mRNAs but in distinct compartments — Regnase-1 cleaves translationally active mRNAs at the ER/ribosome via UPF1 helicase, while Roquin acts in P-bodies/stress granules — resolving how two seemingly redundant pathways cooperate.

    Evidence Subcellular fractionation, single-molecule imaging, UPF1 knockdown, polysome association

    PMID:26000482

    Open questions at the time
    • How Regnase-1 is recruited to specific translating mRNAs vs. bulk translation unknown
    • Stoichiometry of UPF1–Regnase-1 complex at the ribosome unresolved
    • Whether other helicases substitute for UPF1 untested
  8. 2015 High

    Expansion of the target repertoire to IL-17 receptor subunits (Il17ra, Il17rc) and identification of 3′ UTR-independent degradation demonstrated that Regnase-1 acts as a feedback inhibitor of IL-17 signaling at multiple levels.

    Evidence MCPIP1 haploinsufficient mice, mRNA stability assay, domain mutagenesis, genetic epistasis with Il17ra KO

    PMID:26320658

    Open questions at the time
    • Mechanism of 3′ UTR-independent target recognition not defined
    • Whether coding-region stem-loops serve as recognition elements unknown
  9. 2017 High

    Identification of TfR1 and PHD3 as direct Regnase-1 targets linked its endoribonuclease activity to iron homeostasis and HIF signaling, demonstrating functions far beyond cytokine mRNA decay.

    Evidence Regnase-1 KO mice with iron metabolism phenotyping, mRNA stability assay, genetic epistasis

    PMID:28538180

    Open questions at the time
    • Whether iron dysregulation contributes to immunological phenotypes of KO mice unclear
    • Full scope of metabolic targets unknown
  10. 2018 High

    Biochemical reconstitution quantified Regnase-1's RNA binding affinity (~10 nM Kd for stem-loop substrates) and demonstrated that it oligomerizes during RNA interaction, with the zinc finger enhancing stem-loop recognition; separately, Regnase-1 was shown to suppress translation post-initiation in addition to cleaving mRNA.

    Evidence Equilibrium binding measurements, SEC for oligomerization, polysome profiling with CrPV-IRES reporter

    PMID:29471506 PMID:29743536

    Open questions at the time
    • Structural basis of oligomerization unknown
    • Whether translational suppression is separable from cleavage in vivo unresolved
    • Contribution of translational silencing vs. decay to target regulation not quantified
  11. 2019 High

    The molecular basis of UPF1 cooperation was resolved: Regnase-1 binds SMG1-phosphorylated UPF1 via its RNase domain while an intrinsically disordered segment enhances UPF1 helicase activity, and IL-17 signaling was shown to phosphorylate Regnase-1 via Act1–TBK1/IKKi, releasing it from the ER and abolishing its function.

    Evidence Single-molecule imaging, in vitro helicase/cleavage assays, CRISPR phospho-mutant knock-in mice with in vivo inflammation models

    PMID:31072819 PMID:31329944

    Open questions at the time
    • Whether ER-to-cytosol translocation involves other chaperones/cofactors
    • Structural model of UPF1–Regnase-1 complex lacking
    • How IL-17-induced phosphorylation is reversed to restore Regnase-1 function unknown
  12. 2019 High

    Genome-scale CRISPR screening in CD8+ T cells identified BATF as a key downstream mediator of Regnase-1's control of T cell fitness, establishing Regnase-1 as a checkpoint for anti-tumor T cell function.

    Evidence In vivo pooled CRISPR screen, double-KO epistasis, metabolic assays in CD8+ T cells

    PMID:31827283

    Open questions at the time
    • Whether BATF mRNA is a direct cleavage substrate or indirect target not fully resolved
    • Relative importance of multiple Regnase-1 targets in CD8+ T cell context unknown
  13. 2021 High

    Three regulatory layers were simultaneously clarified: the Roquin-1–Regnase-1 physical interaction surface was mapped (mutations cause autoimmunity), IRAK1-dependent phosphorylation at S494/S513 creates a 14-3-3 binding site that sequesters Regnase-1 from mRNA while protecting it from degradation, and TUT7-mediated uridylation of Regnase-1's own mRNA provides an additional layer of post-transcriptional control of Regnase-1 protein levels.

    Evidence Interaction surface mutagenesis and mouse autoimmunity models; interactome MS with phosphosite mutagenesis and nuclear-cytoplasmic fractionation; TUT7 KO mice with 3′-end sequencing

    PMID:34188032 PMID:34636324 PMID:34811541

    Open questions at the time
    • Whether 14-3-3 sequestration and ER localization are coordinated or independent regulatory modes
    • Kinetic modeling integrating all regulatory inputs lacking
    • Whether TUT7 regulation extends to other cell types beyond macrophages
  14. 2022 High

    Therapeutic exploitation of Regnase-1's self-regulatory stem-loop was demonstrated: antisense oligonucleotides blocking the 3′ UTR stem-loop stabilize Regnase-1 mRNA, boost its protein, and suppress inflammation in ARDS and EAE models, providing proof-of-concept for pharmacological enhancement of endogenous Regnase-1.

    Evidence Antisense morpholino treatment, mRNA stability assay, intratracheal/intracranial delivery in vivo

    PMID:35544597

    Open questions at the time
    • Long-term safety and off-target effects of ASO not assessed
    • Whether chronic Regnase-1 elevation impairs adaptive immunity unknown
    • Pharmacokinetics and tissue specificity of delivery not optimized
  15. 2024 High

    Extension to NK cell biology revealed that Regnase-1 controls anti-tumor IFN-γ production through degradation of OCT2 and IκBζ mRNAs, which form a complex with NF-κB to drive Ifng transcription and CXCL16-mediated NK recruitment.

    Evidence NK cell-specific KO, mRNA target identification, co-IP of OCT2–IκBζ–NF-κB complex, tumor models

    PMID:38821052

    Open questions at the time
    • Whether OCT2 mRNA is directly cleaved by Regnase-1 via canonical stem-loop mechanism not shown biochemically
    • Interplay between NK cell and T cell Regnase-1 regulation in tumors unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for stem-loop selectivity (no RNA-bound co-crystal structure exists), the comprehensive target repertoire across cell types, how multiple phosphorylation-based regulatory inputs are temporally integrated, and whether Regnase-1's translational suppression function is mechanistically separable from its endonuclease activity in vivo.
  • No RNA-bound co-crystal or cryo-EM structure
  • No single-cell-resolved target atlas across immune and non-immune lineages
  • Quantitative kinetic model integrating IKK, MALT1, 14-3-3, TBK1, and TUT7 inputs absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 7 GO:0003723 RNA binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4
Partners
DDX3XIRAK1MALT1RC3H1TUT7UPF1USP10YWHAB
Complex memberships
Regnase-1–14-3-3 complexRegnase-1–Roquin-1 complexRegnase-1–UPF1 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Crystal structure of the MCPIP1 N-terminal conserved domain resolved at 2.0 Å reveals a PIN-like RNase fold; site-specific mutagenesis of acidic residues in the catalytic center abolishes RNase activity, and mutation of positively charged residues on an adjacent arm partially abolishes in vivo RNase activity, identifying the RNA substrate-binding site. X-ray crystallography + site-directed mutagenesis + in vivo RNase activity assay Nucleic acids research High 22561375
2011 IκB kinase (IKK) complex phosphorylates Regnase-1 in response to IL-1R/TLR stimulation, leading to its ubiquitination and proteasomal degradation, thereby releasing inhibition of IL-6 mRNA expression; Regnase-1 also destabilizes its own mRNA via a stem-loop in its 3' UTR, forming a negative feedback loop. Phosphorylation assay, ubiquitination assay, IL-6 mRNA stability measurement, genetic KO and reconstitution Nature immunology High 22037600
2013 T cell receptor stimulation causes MALT1/paracaspase to cleave Regnase-1 at residue R111, inactivating it and freeing T cells from Regnase-1-mediated suppression of mRNAs including c-Rel, Ox40, and Il2. In vitro cleavage assay, mutagenesis mapping of cleavage site, T cell functional assays, conditional KO Cell High 23706741
2014 MALT1 paracaspase also cleaves Roquin upon TCR stimulation, and Regnase-1 and Roquin cooperatively repress a shared set of mRNAs (IL-6, ICOS, c-Rel, IRF4, IκBNS, IκBζ) encoding Th17-promoting factors; cooperation requires RNA binding by Roquin and nuclease activity of Regnase-1. MALT1 cleavage assay, luciferase reporter assay, mutagenesis of nuclease domain, T cell differentiation assays Nature immunology High 25282160
2015 Regnase-1 and Roquin regulate a common stem-loop structure in inflammatory mRNAs but act at spatiotemporally distinct locations: Regnase-1 cleaves translationally active mRNAs at the ribosome/ER and requires UPF1 helicase activity, whereas Roquin controls translationally inactive mRNAs in P-bodies/stress granules independently of UPF1. Subcellular fractionation, ribosome profiling, UPF1 knockdown, single-molecule imaging, RNase activity assays Cell High 26000482
2011 MCPIP1 suppresses miRNA biogenesis by cleaving the terminal loops of precursor miRNAs (pre-miRNAs) via its RNase domain, antagonizing Dicer; it also contains a vertebrate-specific oligomerization domain important for pre-miRNA recognition. In vitro pre-miRNA cleavage assay, domain mutagenesis, Dicer competition assays, Northern blot Molecular cell High 22055188
2013 MCPIP1 possesses broad-spectrum antiviral activity by directly binding and degrading viral RNA (JEV, dengue, sindbis, EMCV, influenza, adenovirus) via its RNase and RNA-binding/oligomerization activities but not its deubiquitinase activity. Viral replication assays, domain-specific mutagenesis, RNA binding and in vitro cleavage assays, MCPIP1 knockdown Nucleic acids research High 23355615
2013 MCPIP1 recruits the deubiquitinase USP10 to NEMO via a direct protein-protein interaction, enabling USP10 to remove linear polyubiquitin chains from NEMO, thereby inhibiting IKK activation and NF-κB signaling following genotoxic stress. Co-immunoprecipitation, deubiquitination assay, siRNA knockdown, NF-κB reporter assays The EMBO journal High 24270572
2019 IL-17 induces phosphorylation of Regnase-1 via an Act1-TBK1/IKKi-dependent signaling axis, causing phosphorylated Regnase-1 to be released from the ER into the cytosol where it loses mRNA-degrading function, leading to expression of IL-17 target genes; CRISPR-generated mice with blocked IL-17-induced phosphorylation sites are resistant to Th17-mediated inflammation. Phosphorylation assays, subcellular fractionation, CRISPR/Cas9 knock-in mice, in vivo inflammation models The Journal of experimental medicine High 31072819
2019 UPF1 must first unwind stem-loop structures in target mRNAs before Regnase-1 can cleave them; Regnase-1 physically associates with SMG1-phosphorylated T28 of UPF1 via its RNase domain, and an intrinsically disordered segment of Regnase-1 binds the UPF1 RecA domain to enhance its helicase activity. Single-molecule imaging, co-immunoprecipitation, in vitro helicase and cleavage assays, SMG1 inhibitor studies, domain mutagenesis Nucleic acids research High 31329944
2021 Roquin-1 physically interacts with Regnase-1 through a defined interaction surface that includes the sanroque residue; mutations disrupting this interaction impair cooperative post-transcriptional repression of target mRNAs and lead to autoimmunity. Co-immunoprecipitation, interaction surface mutagenesis, T cell functional assays, mouse autoimmunity models Nature immunology High 34811541
2021 IL-1β/TLR stimulation dynamically induces formation of a Regnase-1–14-3-3 complex mediated by IRAK1 through a C-terminal domain; phosphorylation of Regnase-1 at S494 and S513 is required for 14-3-3 interaction, which stabilizes Regnase-1 by protecting it from βTRCP-mediated proteasomal degradation but simultaneously inhibits Regnase-1-mRNA association and abolishes mRNA decay; 14-3-3 also abrogates nuclear-cytoplasmic shuttling of Regnase-1. Regnase-1 interactome by MS, Co-IP, phosphosite mutagenesis, mRNA decay assay, nuclear-cytoplasmic fractionation eLife High 34636324
2018 MCPIP1 acts as an endonuclease cleaving stem-loop structures at the loop motif and also single-stranded RNA; it binds target RNAs with ~10 nM affinity (Kd); the zinc finger in the PIN domain increases affinity for 25-nt stem-loop RNA; MCPIP1 undergoes homooligomerization during RNA interaction. In vitro endonuclease assay, equilibrium binding measurements (Kd determination), size-exclusion chromatography, domain deletion analysis Scientific reports High 29743536
2017 Regnase-1 directly degrades mRNAs encoding transferrin receptor 1 (TfR1) and prolyl-hydroxylase-domain protein 3 (PHD3) in vivo, controlling iron homeostasis; loss of Regnase-1 in mice causes iron deficiency anemia via impaired duodenal iron uptake and HIF2α/PHD3 dysregulation; Regnase-1 is itself a HIF2α-inducible gene, providing a positive feedback loop. Regnase-1 KO mice, mRNA stability assay, RNA-seq, iron metabolism phenotyping, genetic epistasis Cell reports High 28538180
2018 In the context of the NFKBIZ translational silencing element (TSE), MCPIP1 suppresses translation (a post-initiation step) in addition to its known endonuclease activity; SL4/5 in the TSE are sufficient for MCPIP1 binding and mRNA destabilization, but SL1-3 are additionally required for translational silencing; MCPIP1 reduces ribosome occupancy and silences even cap-independent (CrPV-IRES) translation. Luciferase reporter assay, polysome profiling, MCPIP1 knockdown/overexpression, IRES reporter Nucleic acids research High 29471506
2015 MCPIP1 endoribonuclease activity (but not deubiquitinase activity) functions as a feedback inhibitor of IL-17 receptor signal transduction and directly degrades Il17ra and Il17rc mRNA independently of the 3' UTR, in addition to degrading Il6 and Nfkbiz mRNAs. MCPIP1 knockdown/haploinsufficient mice, mRNA stability assay, domain mutagenesis, IL-17 signaling reporter assays, genetic epistasis with Il17ra KO Immunity High 26320658
2017 MCPIP1 directly binds and cleaves C/EBPβ mRNA via endonucleolytic cleavage of stem-loop structures in the 3' UTR, as demonstrated by in vitro cleavage assay, luciferase reporter assay, and RNA immunoprecipitation. In vitro cleavage assay, luciferase-reporter assay, RNA immunoprecipitation (RIP) PloS one High 28328949
2011 MCPIP1 suppresses stress granule (SG) formation and sensitizes cells to apoptosis under stress; SG repression is dependent on MCPIP1 deubiquitinating activity and involves negative regulation of eIF2α phosphorylation. MCPIP1 overexpression/KO, SG imaging, eIF2α phosphorylation assay, deubiquitinase domain mutagenesis The Journal of biological chemistry Medium 21971051
2013 MCPIP1 restricts HIV-1 production in CD4+ T cells by decreasing steady-state viral mRNA levels through its RNase domain; common T-cell stimuli induce rapid proteasomal degradation of MCPIP1, removing this restriction. Ectopic MCPIP1 expression, MCPIP1 siRNA knockdown, viral mRNA quantification, proteasome inhibitor (MG132) rescue, primary T cell assays Proceedings of the National Academy of Sciences of the United States of America High 24191027
2014 MCPIP1 directly colocalizies with HCV RNA, can degrade HCV RNA in vitro, and its RNA binding, oligomerization, and RNase activities (but not deubiquitinase) are required to suppress HCV replication. Immunocytochemistry co-localization, in vitro RNA cleavage assay, domain mutagenesis, knockdown/overexpression, replication-defective HCV mutant Journal of immunology High 25225661
2016 MCPIP1 degrades IL-8 mRNA through its RNase activity targeting stem-loop/hairpin structures in the IL-8 3' UTR, as shown with purified recombinant MCPIP1 protein in an in vitro cleavage assay. Recombinant protein purification, in vitro mRNA cleavage assay, 3'UTR reporter analysis Journal of innate immunity High 27513529
2021 TUT7 (terminal uridyltransferase 7) directly binds the stem-loop structure in the Zc3h12a (Regnase-1) 3' UTR following TLR4 activation, promoting uridylation and degradation of Regnase-1 mRNA, thereby controlling Regnase-1 protein levels and downstream IL-6 expression. TUT7 KO mice, RNA immunoprecipitation, 3'-end sequencing (oligo-uridylation detection), TLR4 stimulation assays Nature communications High 34188032
2019 Regnase-1 directly targets Tcf7 (encoding TCF-1) mRNA; its deficiency augments TCF-1 expression in CD8+ T cells, promoting formation of TCF-1+ precursor exhausted T cells with enhanced persistence. Regnase-1 conditional KO, mRNA stability assays, transcriptional/epigenetic profiling, xenograft tumor models Blood Medium 33690816
2019 BATF is identified as a key transcriptional target of Regnase-1 in CD8+ T cells; loss of BATF suppresses the increased accumulation and mitochondrial fitness of Regnase-1-deficient CD8+ T cells, placing BATF downstream of Regnase-1 by genetic epistasis. In vivo pooled CRISPR-Cas9 screen, secondary genome-scale CRISPR screen, double-KO epistasis, metabolic assays Nature High 31827283
2019 Regnase-1 regulates HSPC self-renewal by degrading Gata2 and Tal1 mRNAs; loss of Regnase-1 in HSPCs leads to rapid abnormal hematopoiesis. Conditional KO mice, mRNA stability assay, bone marrow transplantation, RNA-seq Nature communications Medium 30842549
2016 KSHV and EBV precursor miRNAs are directly cleaved by MCPIP1's RNase domain; KSHV infection represses MCPIP1 expression, and KSHV-encoded miRNAs target the MCPIP1 3' UTR to suppress its expression, representing a viral immune evasion mechanism. In vitro pre-miRNA cleavage assay, siRNA knockdown, luciferase 3'UTR reporter, de novo KSHV infection model PLoS biology High 27893764
2015 IL-17 stabilizes Zc3h12a mRNA via a CIKS–DDX3X complex; IL-17 stimulation promotes CIKS–DDX3X interaction (requiring the DDX3X helicase domain), DDX3X directly binds Zc3h12a mRNA, and IKKε, TRAF2, and TRAF5 are also required for this stabilization. Co-immunoprecipitation, DDX3X knockdown, mRNA half-life assay, RNA immunoprecipitation Journal of immunology Medium 25710910
2021 Regnase-1 suppresses mRNAs encoding Gata3 and Egr1 in ILC2s to control their profibrotic function; Regnase-1-deficient ILC2s spontaneously proliferate and activate and augment bleomycin-induced pulmonary fibrosis. Competitive bone marrow transfer, RNA-seq of Regnase-1-deficient ILC2s, bleomycin fibrosis model, mRNA target validation The European respiratory journal Medium 32978308
2020 IKK complex-mediated phosphorylation of Regnase-1 at S435/S439 is essential for IL-33- and IL-25-induced ILC2 activation; Regnase-1 S435A/S439A knock-in mice retain Regnase-1 protein and show reduced ILC2 proliferation, cytokine production, and type 2 pulmonary inflammation in vivo. Phospho-mutant knock-in mice (S435A/S439A), ILC2 stimulation assays, in vivo cytokine challenge models JCI insight High 31990689
2017 MCPIP1 regulates C/EBPβ and C/EBPδ mRNA levels as direct targets of its RNase activity in macrophages, and pharmacological inhibition of MALT1 (which cleaves MCPIP1) increases MCPIP1 protein and protects mice from LPS-induced lung injury. Myeloid-specific KO mice, mRNA stability assay, MI-2 MALT1 inhibitor treatment, in vivo LPS model Signal transduction and targeted therapy Medium 29263935
2018 Regnase-1 controls colon epithelial regeneration by regulating mTORC1 signaling and purine metabolism; intestinal epithelial-specific deletion of Regnase-1 increases cell proliferation, decreases apoptosis, and attenuates DSS-induced colitis and tumor progression. Intestinal epithelial-specific KO mice, metabolomics, mTOR pathway analysis, DSS colitis model Proceedings of the National Academy of Sciences of the United States of America Medium 30297433
2024 Regnase-1 deletion in NK cells increases anti-tumor IFN-γ production via elevated OCT2 and IκBζ mRNA targets; OCT2 and IκBζ form a complex with NF-κB to induce Ifng transcription, and IFN-γ induces CXCL16 on myeloid cells to recruit CXCR6+ NK cells. NK cell-specific Regnase-1 KO, mRNA target identification, co-IP of OCT2-IκBζ-NF-κB complex, in vivo tumor models Immunity High 38821052
2010 IL-1β induces ZC3H12A/MCPIP1 expression through the MAP kinase pathway and transcription factors Elk-1 and SRF, which bind a ZC3H12A promoter region from -76 to +60; chromatin immunoprecipitation confirmed in vivo binding of both Elk-1 and SRF to this promoter region. Reporter assay with promoter deletion constructs, ChIP, MAP kinase pathway inhibitors, primary macrophages BMC molecular biology Medium 20137095
2022 Antisense morpholino oligonucleotides targeting the stem-loop structures in Regnase-1's own 3'UTR block Regnase-1 self-regulation, stabilizing Regnase-1 mRNA and increasing Regnase-1 protein, which then degrades multiple proinflammatory target mRNAs; intratracheal or intracranial delivery ameliorates inflammatory disease in vivo. Antisense oligonucleotide treatment, mRNA stability assay, macrophage cytokine profiling, in vivo ARDS and EAE models Science translational medicine High 35544597
2022 Macrophage-specific Mcpip1 deficiency arrests monocyte-to-macrophage maturation via an ATF3–AP1S2 signaling axis; silencing Ap1s2 or Atf3 suppressed MCPIP1-deficient macrophage M1-like polarization and cytokine production, and in vivo blockage of Ap1s2 ameliorated DSS colitis. scRNA-seq, macrophage-specific KO, RNA-seq, CUT&Tag, luciferase assay, in vivo colitis model with Ap1s2 blockage Gut High 37015751

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 352 31827283
2015 Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms. Cell 318 26000482
2013 Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell 293 23706741
2011 The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nature immunology 243 22037600
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
2011 MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation. Molecular cell 220 22055188
2014 MiR-9 promotes microglial activation by targeting MCPIP1. Nature communications 152 25019481
2015 MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation. Immunity 128 26320658
2018 circRNA Mediates Silica-Induced Macrophage Activation Via HECTD1/ZC3H12A-Dependent Ubiquitination. Theranostics 121 29290828
2013 MCPIP1 ribonuclease exhibits broad-spectrum antiviral effects through viral RNA binding and degradation. Nucleic acids research 113 23355615
2013 USP10 inhibits genotoxic NF-κB activation by MCPIP1-facilitated deubiquitination of NEMO. The EMBO journal 96 24270572
2012 MCPIP1 down-regulates IL-2 expression through an ARE-independent pathway. PloS one 86 23185455
2016 Macrophage-derived MCPIP1 mediates silica-induced pulmonary fibrosis via autophagy. Particle and fibre toxicology 83 27782836
2012 Structural study of MCPIP1 N-terminal conserved domain reveals a PIN-like RNase. Nucleic acids research 79 22561375
2012 Monocyte chemotactic protein-1-induced protein-1 (MCPIP1) is a novel multifunctional modulator of inflammatory reactions. Biochimica et biophysica acta 77 22771441
2017 MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression. Cancer research 76 28716897
2021 Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood 74 33690816
2013 mRNA degradation by the endoribonuclease Regnase-1/ZC3H12a/MCPIP-1. Biochimica et biophysica acta 72 23500036
2016 MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation. Journal of immunology (Baltimore, Md. : 1950) 71 27920272
2013 MCPIP1 restricts HIV infection and is rapidly degraded in activated CD4+ T cells. Proceedings of the National Academy of Sciences of the United States of America 67 24191027
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
2017 MCPIP1 contributes to clear cell renal cell carcinomas development. Angiogenesis 66 28197812
2010 Transcription factors Elk-1 and SRF are engaged in IL1-dependent regulation of ZC3H12A expression. BMC molecular biology 64 20137095
2017 Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses. Cellular & molecular immunology 63 28194024
2022 MCPIP1 restrains mucosal inflammation by orchestrating the intestinal monocyte to macrophage maturation via an ATF3-AP1S2 axis. Gut 60 37015751
2022 Regnase-1 Prevents Pulmonary Arterial Hypertension Through mRNA Degradation of Interleukin-6 and Platelet-Derived Growth Factor in Alveolar Macrophages. Circulation 58 35997026
2017 Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury. Signal transduction and targeted therapy 58 29263935
2017 Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs. Cell reports 57 28538180
2014 MCPIP1 suppresses hepatitis C virus replication and negatively regulates virus-induced proinflammatory cytokine responses. Journal of immunology (Baltimore, Md. : 1950) 57 25225661
2019 Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response. The Journal of experimental medicine 53 31072819
2015 RGS2 suppresses breast cancer cell growth via a MCPIP1-dependent pathway. Journal of cellular biochemistry 51 25187114
2013 Targeted disruption of MCPIP1/Zc3h12a results in fatal inflammatory disease. Immunology and cell biology 51 23567898
2021 Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses. Nature immunology 50 34811541
2019 CCL2 promotes macrophages-associated chemoresistance via MCPIP1 dual catalytic activities in multiple myeloma. Cell death & disease 49 31611552
2019 Translation-dependent unwinding of stem-loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs. Nucleic acids research 47 31329944
2021 Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase-1. The European respiratory journal 46 32978308
2017 Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis. Journal of immunology (Baltimore, Md. : 1950) 43 29127149
2011 Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress. The Journal of biological chemistry 43 21971051
2016 MCPIP1 RNase Is Aberrantly Distributed in Psoriatic Epidermis and Rapidly Induced by IL-17A. The Journal of investigative dermatology 41 27180111
2015 miR-139 modulates MCPIP1/IL-6 expression and induces apoptosis in human OA chondrocytes. Experimental & molecular medicine 40 26450708
2013 MCPIP1 negatively regulates toll-like receptor 4 signaling and protects mice from LPS-induced septic shock. Cellular signalling 40 23422584
2016 MCPIP1 Regulates Alveolar Macrophage Apoptosis and Pulmonary Fibroblast Activation After in vitro Exposure to Silica. Toxicological sciences : an official journal of the Society of Toxicology 39 26865670
2018 Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism. Proceedings of the National Academy of Sciences of the United States of America 38 30297433
2015 CIKS/DDX3X interaction controls the stability of the Zc3h12a mRNA induced by IL-17. Journal of immunology (Baltimore, Md. : 1950) 36 25710910
2016 MCPIP-1, Alias Regnase-1, Controls Epithelial Inflammation by Posttranscriptional Regulation of IL-8 Production. Journal of innate immunity 35 27513529
2015 The Role of MCPIP1 in Ischemia/Reperfusion Injury-Induced HUVEC Migration and Apoptosis. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 26329288
2019 MiR-421 promotes the development of osteosarcoma by regulating MCPIP1 expression. Cancer biology & therapy 34 31718519
2022 Resistance to tyrosine kinase inhibitors promotes renal cancer progression through MCPIP1 tumor-suppressor downregulation and c-Met activation. Cell death & disease 33 36138026
2019 MCP-1 mediates ischemia-reperfusion-induced cardiomyocyte apoptosis via MCPIP1 and CaSR. American journal of physiology. Heart and circulatory physiology 33 31774703
2016 Modulation of influenza A virus replication by microRNA-9 through targeting MCPIP1. Journal of medical virology 33 27322373
2013 Involvement of miR-9/MCPIP1 axis in PDGF-BB-mediated neurogenesis in neuronal progenitor cells. Cell death & disease 33 24336080
2016 Virus-Mediated Alterations in miRNA Factors and Degradation of Viral miRNAs by MCPIP1. PLoS biology 32 27893764
2013 Regnase-1, a ribonuclease involved in the regulation of immune responses. Cold Spring Harbor symposia on quantitative biology 32 24163394
2017 Endonuclease Regnase-1/Monocyte chemotactic protein-1-induced protein-1 (MCPIP1) in controlling immune responses and beyond. Wiley interdisciplinary reviews. RNA 31 28929622
2018 Substrate specificity of human MCPIP1 endoribonuclease. Scientific reports 30 29743536
2019 Regnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis. Nature communications 28 30842549
2019 Activity of MCPIP1 RNase in tumor associated processes. Journal of experimental & clinical cancer research : CR 28 31639017
2015 Mmu-miR-27a-5p-Dependent Upregulation of MCPIP1 Inhibits the Inflammatory Response in LPS-Induced RAW264.7 Macrophage Cells. BioMed research international 28 26295043
2019 Minocycline protects against myocardial ischemia/reperfusion injury in rats by upregulating MCPIP1 to inhibit NF-κB activation. Acta pharmacologica Sinica 27 30792486
2015 MCPIP1 mediates silica-induced cell migration in human pulmonary fibroblasts. American journal of physiology. Lung cellular and molecular physiology 27 26608530
2020 Regnase-1 degradation is crucial for IL-33- and IL-25-mediated ILC2 activation. JCI insight 26 31990689
2013 Proteasome inhibitor MG-132 induces MCPIP1 expression. The FEBS journal 26 23551903
2020 MCPIP1 RNase and Its Multifaceted Role. International journal of molecular sciences 25 33003343
2019 MCPIP1 alleviated lipopolysaccharide-induced liver injury by regulating SIRT1 via modulation of microRNA-9. Journal of cellular physiology 25 31099043
2016 Role of MCPIP1 in the Endothelial-Mesenchymal Transition Induced by Silica. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 25 27866190
2022 MCPIP1 promotes cell proliferation, migration and angiogenesis of glioma via VEGFA-mediated ERK pathway. Experimental cell research 24 35752346
2016 Regnase-1 in microglia negatively regulates high mobility group box 1-mediated inflammation and neuronal injury. Scientific reports 24 27044405
2015 Monocyte Chemoattractant Protein-Induced Protein 1 (MCPIP1) Enhances Angiogenic and Cardiomyogenic Potential of Murine Bone Marrow-Derived Mesenchymal Stem Cells. PloS one 24 26214508
2021 Regnase-1 is essential for B cell homeostasis to prevent immunopathology. The Journal of experimental medicine 23 33822844
2013 Interleukin-17 (IL-17) and IL-1 activate translation of overlapping sets of mRNAs, including that of the negative regulator of inflammation, MCPIP1. The Journal of biological chemistry 23 23658019
2021 Regnase-1-related endoribonucleases in health and immunological diseases. Immunological reviews 22 34514623
2018 Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia. Mucosal immunology 22 29695841
2017 ZC3H12A/MCPIP1/Regnase-1-related endonucleases: An evolutionary perspective on molecular mechanisms and biological functions. BioEssays : news and reviews in molecular, cellular and developmental biology 22 28719000
2016 Histone deacetylase inhibitor vorinostat (SAHA, MK0683) perturb miR-9-MCPIP1 axis to block IL-1β-induced IL-6 expression in human OA chondrocytes. Connective tissue research 22 27404795
2022 Enhancement of Regnase-1 expression with stem loop-targeting antisense oligonucleotides alleviates inflammatory diseases. Science translational medicine 21 35544597
2018 A translational silencing function of MCPIP1/Regnase-1 specified by the target site context. Nucleic acids research 21 29471506
2017 MCPIP1, alias Regnase-1 binds and cleaves mRNA of C/EBPβ. PloS one 21 28328949
2024 Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng. Immunity 20 38821052
2012 Differential regulation by Toll-like receptor agonists reveals that MCPIP1 is the potent regulator of innate immunity in bacterial and viral infections. Journal of innate immunity 20 22777400
2019 Keratinocyte-specific ablation of Mcpip1 impairs skin integrity and promotes local and systemic inflammation. Journal of molecular medicine (Berlin, Germany) 19 31786670
2017 MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma. Journal of cellular biochemistry 19 27935099
2021 Elevated linc00936 or silenced microRNA-425-3p inhibits immune escape of gastric cancer cells via elevation of ZC3H12A. International immunopharmacology 18 33756228
2021 Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation. Nature communications 18 34188032
2021 Loss of epidermal MCPIP1 is associated with aggressive squamous cell carcinoma. Journal of experimental & clinical cancer research : CR 18 34903245
2017 MCPIP1 attenuates the innate immune response to influenza A virus by suppressing RIG-I expression in lung epithelial cells. Journal of medical virology 18 28892164
2021 MCPIP-1 Restricts Inflammation via Promoting Apoptosis of Neutrophils. Frontiers in immunology 17 33717148
2020 The anti-inflammatory protein MCPIP1 inhibits the development of ccRCC by maintaining high levels of tumour suppressors. European journal of pharmacology 17 32971087
2017 MCPIP1 inhibits coxsackievirus B3 replication by targeting viral RNA and negatively regulates virus-induced inflammation. Medical microbiology and immunology 17 29043433
2010 ZC3H12A (MCPIP1): molecular characteristics and clinical implications. Clinica chimica acta; international journal of clinical chemistry 17 20807520
2021 Deletion of Mcpip1 in Mcpip1fl/flAlbCre mice recapitulates the phenotype of human primary biliary cholangitis. Biochimica et biophysica acta. Molecular basis of disease 16 33513427
2021 Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation. Disease models & mechanisms 16 33737335
2021 Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation. Frontiers in immunology 16 34659213
2018 MCPIP1-induced autophagy mediates ischemia/reperfusion injury in endothelial cells via HMGB1 and CaSR. Scientific reports 16 29379093
2017 Ectopic overexpression of MCPIP1 impairs adipogenesis by modulating microRNAs. Biochimica et biophysica acta. Molecular cell research 16 28939056
2015 MCPIP1 Regulates Fibroblast Migration in 3-D Collagen Matrices Downstream of MAP Kinases and NF-κB. The Journal of investigative dermatology 16 26399696
2020 MCPIP1 inhibits Hepatitis B virus replication by destabilizing viral RNA and negatively regulates the virus-induced innate inflammatory responses. Antiviral research 15 31926181
2020 How are MCPIP1 and cytokines mutually regulated in cancer-related immunity? Protein & cell 15 32548715
2011 Post-transcriptional regulation of IL-6 production by Zc3h12a in fibroblast-like synovial cells. Clinical and experimental rheumatology 15 22132693
2023 miR-143-3p shuttled by M2 macrophage-derived extracellular vesicles induces progression of colorectal cancer through a ZC3H12A/C/EBPβ axis-dependent mechanism. International immunopharmacology 14 37126984
2021 IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay. eLife 14 34636324