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Showing ZC3H12A — MCPIP1 is a alias.

ZC3H12A

Endoribonuclease ZC3H12A · UniProt Q5D1E8

Length
599 aa
Mass
65.7 kDa
Annotated
2026-06-11
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZC3H12A (MCPIP1/Regnase-1) is an endoribonuclease that resolves inflammation and maintains immune and metabolic homeostasis by selectively degrading a defined set of mRNAs through recognition and cleavage of stem-loop structures in their 3'-UTRs (PMID:19322177, PMID:29743536). It engages substrates at the loop motif of stem-loops and also cuts single-stranded RNA, with a PIN-domain zinc finger enhancing affinity (Kd ~10 nM) and homooligomerization accompanying RNA binding (PMID:29743536). Catalytically, it requires UPF1 to unwind target stem-loops before cleavage, contacting SMG1-phosphorylated UPF1 through its RNase domain and an intrinsically disordered segment that stimulates UPF1 helicase activity, and it acts on translationally active mRNAs at the ribosome/ER—distinct from the partner protein Roquin, which acts on translationally inactive transcripts in P-bodies/stress granules (PMID:26000482, PMID:31329944). Its substrate repertoire spans inflammatory and immune transcripts (Il6, Il12p40, c-Rel, Nfkbiz/IκBζ, Tcf7, POU2F2/OCT2), iron-handling mRNAs (TfR1, PHD3), and hematopoietic and lineage regulators (Gata2, Tal1, Gata3, Egr1), making it a hub controlling T cell, ILC2, NK cell, neutrophil, macrophage, and HSPC programs (PMID:19322177, PMID:28538180, PMID:31827283, PMID:30842549, PMID:38821052, PMID:33717148, PMID:32978308). Beyond mRNA decay it cleaves pre-miRNA terminal loops to antagonize Dicer and degrades viral RNA, both via the same RNase activity (PMID:22055188, PMID:23355615, PMID:25225661). Regnase-1 is itself tightly controlled: TCR-activated MALT1 cleaves it at R111 to de-repress targets, IL-1R/TLR-induced IKK phosphorylation at S435/S439 triggers β-TrCP-mediated proteasomal degradation while IRAK1-driven phosphorylation promotes 14-3-3 binding, and IL-17/Act1-TBK1/IKKi phosphorylation releases it from the ER into the cytosol to inactivate it (PMID:23706741, PMID:31072819, PMID:34636324, PMID:31990689). It also enforces feedback on its own expression by degrading its own mRNA through a 3'-UTR stem-loop (PMID:35544597).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2009 High

    Established the founding activity: an unknown LPS-induced protein was shown to be an RNase that selectively degrades inflammatory mRNAs through their 3'-UTRs, defining ZC3H12A as a post-transcriptional brake on inflammation.

    Evidence Macrophage overexpression/KO, mRNA stability and 3'-UTR reporter assays, RNase assay on purified protein

    PMID:19322177

    Open questions at the time
    • 3'-UTR sequence/structure determinant of substrate selection not yet defined
    • structural basis of catalysis not resolved
  2. 2011 High

    Extended the enzyme's reach beyond mRNA by showing it cleaves pre-miRNA terminal loops to antagonize Dicer, and identified a vertebrate-specific oligomerization domain for substrate recognition.

    Evidence In vitro pre-miRNA cleavage, RNase-domain mutagenesis, miRNA profiling in mammalian cells

    PMID:22055188

    Open questions at the time
    • physiological scope of miRNA regulation in vivo unclear
    • selectivity between pre-miRNA and mRNA substrates undefined
  3. 2010 Medium

    Defined how the gene is induced, placing it downstream of IL-1β/MAPK signaling via Elk-1/SRF promoter occupancy.

    Evidence Promoter reporter assay, signaling inhibitors, ChIP for Elk-1 and SRF

    PMID:20137095

    Open questions at the time
    • additional transcriptional inputs not mapped
    • link between induction kinetics and inflammatory resolution untested
  4. 2013 High

    Revealed a second, RNase-independent activity (deubiquitination via USP10 recruitment to NEMO) and showed antiviral and TCR-regulated functions, broadening the protein from an mRNA decay enzyme to a multifunctional immune regulator.

    Evidence Co-IP/ubiquitin chain analysis (NEMO/USP10), viral and HIV-1 RNA degradation assays with domain mutants, MALT1 cleavage assay at R111 with conditional KO

    PMID:23355615 PMID:23706741 PMID:24191027 PMID:24270572

    Open questions at the time
    • whether ZC3H12A has intrinsic deubiquitinase catalysis vs. adaptor role unresolved
    • in vivo significance of antiviral RNA degradation versus mRNA decay not separated
  5. 2015 High

    Resolved the spatial logic of substrate selection: ZC3H12A acts on translationally active mRNAs at the ribosome/ER in a UPF1-dependent manner, cooperating with Roquin which acts on translationally silent mRNAs in P-bodies, and operates in IL-17 receptor feedback.

    Evidence Subcellular fractionation, ribosome profiling, UPF1 knockdown, RNase-dead mutant epistasis in IL-17 signaling

    PMID:26000482 PMID:26320658

    Open questions at the time
    • mechanism coupling translation status to cleavage not yet biochemically reconstituted
    • how 3'-UTR-independent Il17ra/Il17rc degradation occurs unexplained
  6. 2018 High

    Characterized the catalytic enzymology with purified protein, defining loop-motif cleavage, ssRNA activity, PIN-domain zinc finger contribution, oligomerization, and nanomolar affinity; also uncovered context-dependent translational silencing beyond decay.

    Evidence In vitro endonuclease and Kd assays, size-exclusion chromatography, active-site mutagenesis (D141N); polysome profiling with NFKBIZ TSE mutants

    PMID:29471506 PMID:29743536

    Open questions at the time
    • high-resolution structure of enzyme-RNA complex not determined
    • how decay versus translational silencing is selected on the same transcript unclear
  7. 2017 Medium

    Expanded physiological targets into iron homeostasis and additional inflammatory transcripts, including a HIF2α-PHD3 feedback loop, establishing the enzyme as a metabolic as well as immune regulator.

    Evidence Regnase-1 KO mice with iron phenotyping and TfR1/PHD3 mRNA stability assays; in vitro cleavage/RIP for C/EBPβ and IL-8 mRNAs

    PMID:27513529 PMID:28328949 PMID:28538180

    Open questions at the time
    • tissue-specific target hierarchy not defined
    • some target validations rest on single-lab in vitro cleavage
  8. 2019 High

    Mapped the full post-translational control network and the molecular basis of UPF1 cooperation, and extended substrate control to hematopoiesis and T cell exhaustion programs.

    Evidence Single-molecule imaging and interaction mapping (UPF1/SMG1); phospho-mutant knockin mice (Act1-TBK1/IKKi and IKK/β-TrCP/IRAK1-14-3-3 axes); conditional KO targeting Gata2/Tal1 and Tcf7 with genome-scale screen

    PMID:30842549 PMID:31072819 PMID:31329944 PMID:31827283 PMID:34636324

    Open questions at the time
    • integration of competing phospho-signals in vivo not quantitatively modeled
    • cross-talk between localization control and substrate choice incompletely defined
  9. 2021 High

    Defined feedback regulation of Regnase-1 mRNA itself and the Roquin physical interaction surface, and broadened cell-type functions into ILC2s, neutrophils, and renal cancer.

    Evidence TUT7 KO mice with 3'-end sequencing and direct RNA binding; CIKS-DDX3X RIP/Co-IP; Roquin-1 interaction-surface mutagenesis with knockin mice; ILC2 phospho-mutant and neutrophil/ccRCC conditional models

    PMID:25710910 PMID:31990689 PMID:33717148 PMID:34188032 PMID:34657130 PMID:34811541

    Open questions at the time
    • relative contribution of mRNA uridylation versus self-cleavage to Regnase-1 turnover unresolved
    • structural detail of the Roquin-Regnase-1 complex absent
  10. 2024 High

    Demonstrated lineage-specific control of effector transcription by degrading OCT2 (POU2F2) and IκBζ mRNAs in NK cells, and gut macrophage maturation via the ATF3-AP1S2 axis, reinforcing the enzyme as a tunable controller of immune effector programs.

    Evidence NK cell- and macrophage-specific KO, scRNA-seq/CUT&Tag, Co-IP of OCT2-IκBζ-NF-κB complex, in vivo tumor and colitis models

    PMID:37015751 PMID:38821052

    Open questions at the time
    • whether these target sets are direct stem-loop substrates in each lineage not fully established
    • therapeutic window of targeting Regnase-1 across cell types unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of ZC3H12A bound to a stem-loop substrate together with UPF1, and a unifying model of how phosphorylation, localization, and translation status jointly dictate substrate choice, remain to be established.
  • no atomic structure of the catalytically engaged enzyme-RNA-UPF1 complex
  • quantitative integration of competing regulatory inputs lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 6 GO:0003723 RNA binding 4 GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2 GO:0005840 ribosome 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-162582 Signal Transduction 3
Partners
14-3-3DDX3XMALT1NEMO/IKBKGROQUIN/RC3H1TUT7/ZCCHC6UPF1USP10

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Zc3h12a/MCPIP1/Regnase-1 is an RNase that directly degrades inflammatory mRNAs (including Il6, Il12p40, Calcr) via their 3'-UTR stem-loop structures; expressed protein showed RNase activity and accelerated Il6 mRNA degradation in a 3'-UTR-dependent manner in macrophages. Overexpression/knockout in macrophages, mRNA stability assays, 3'-UTR reporter assays, RNase activity assay on purified protein Nature High 19322177
2013 In T cells, TCR stimulation leads to cleavage of Regnase-1 at residue R111 by the paracaspase Malt1, inactivating Regnase-1 and de-repressing target mRNAs including c-Rel, Ox40, and Il2 via their 3'-UTRs. Co-IP, cleavage assay, mutagenesis of cleavage site (R111), T cell-specific conditional KO, mRNA stability assays Cell High 23706741
2014 Upon TCR stimulation, the paracaspase MALT1 cleaves both Roquin and Regnase-1 proteins, cooperatively de-repressing shared target mRNAs (IL-6, ICOS, c-Rel, IRF4, IκBNS, IκBζ) to promote Th17 differentiation; cooperation requires RNA binding by Roquin and the nuclease activity of Regnase-1. MALT1 cleavage assays, nuclease-dead Regnase-1 mutant, mRNA stability reporter assays, T cell differentiation assays Nature immunology High 25282160
2015 Regnase-1 and Roquin regulate overlapping sets of inflammatory mRNAs via a common stem-loop structure but function in distinct subcellular compartments: Regnase-1 associates with the ribosome/endoplasmic reticulum and specifically degrades translationally active mRNAs in a UPF1 helicase-dependent manner, whereas Roquin acts at processing bodies/stress granules on translationally inactive mRNAs independently of UPF1. Subcellular fractionation, ribosome profiling, UPF1 knockdown, live imaging, co-IP, mRNA decay 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 activity; MCPIP1 also possesses a vertebrate-specific oligomerization domain important for pre-miRNA recognition. In vitro pre-miRNA cleavage assay, mutagenesis of RNase domain, overexpression/knockdown in mammalian cells, miRNA profiling Molecular cell High 22055188
2013 MCPIP1 facilitates deubiquitination of NEMO via USP10 to terminate genotoxic NF-κB signaling: upon DNA damage, MCPIP1 interacts with NEMO and recruits USP10, which removes linear polyubiquitin chains from NEMO, suppressing IKK/NF-κB activation. Co-IP (MCPIP1-NEMO-USP10 interaction), ubiquitin chain analysis, NF-κB reporter assays, USP10 KD epistasis The EMBO journal Medium 24270572
2013 MCPIP1 possesses broad-spectrum antiviral activity through its RNase domain by directly binding and degrading viral RNA; RNA binding, RNase activity, and oligomerization are all required, but deubiquitinase activity is not. Viral RNA cleavage assay, MCPIP1 overexpression/knockdown in virus-infected cells, domain mutant analysis (RNase-dead, oligomerization-deficient) Nucleic acids research High 23355615
2019 IL-17 induces phosphorylation of Regnase-1 at specific serine residues via an Act1-TBK1/IKKi signaling axis, causing Regnase-1 to be released from the endoplasmic reticulum into the cytosol and losing its mRNA degradation function, thereby allowing IL-17 target gene expression. Phosphorylation mapping, CRISPR/Cas9 knockin of phospho-deficient Regnase-1 mutant mice, subcellular fractionation, IL-17 response assays The Journal of experimental medicine High 31072819
2017 Regnase-1 is essential for iron homeostasis by degrading TfR1 mRNA and PHD3 mRNA; Regnase-1-deficient mice develop severe iron deficiency anemia due to impaired duodenal iron uptake, and Regnase-1 is itself a HIF2α-inducible gene providing a positive feedback loop via PHD3 suppression. Regnase-1 KO mice, mRNA stability assay for TfR1 and PHD3, iron metabolism phenotyping, transcriptome analysis Cell reports High 28538180
2019 UPF1 is required to unwind stem-loop structures in target mRNAs to license Regnase-1 to proceed with endoribonucleolytic cleavage; Regnase-1 physically associates with UPF1 at two distinct points: its RNase domain binds SMG1-phosphorylated T28 in UPF1, and an intrinsically disordered segment binds the UPF1 RecA domain to enhance UPF1 helicase activity. Single-molecule imaging, co-IP, domain mutagenesis, SMG1 inhibitor treatment, dendritic cell mRNA decay assays Nucleic acids research High 31329944
2019 In IL-1R/TLR-stimulated cells, Regnase-1 is phosphorylated by IKKs at S435/S439, recognized by β-TrCP, and degraded via the ubiquitin-proteasome pathway; additionally, IRAK1-dependent phosphorylation at S494/S513 promotes Regnase-1 interaction with 14-3-3, which inhibits Regnase-1 mRNA association and mRNA decay activity while protecting Regnase-1 from β-TrCP-mediated degradation; 14-3-3 also abrogates Regnase-1 nuclear-cytoplasmic shuttling. Regnase-1 interactome analysis (MS), Co-IP, phospho-site mutagenesis, mRNA decay assays eLife High 34636324
2018 MCPIP1 acts as an endonuclease cleaving stem-loop structures at the loop motif and also cleaves single-stranded RNA; the zinc finger in the PIN domain increases affinity for 25-nt stem-loop RNA; MCPIP1 undergoes homooligomerization during interaction with RNA substrates; Kd for RNA targets is approximately 10 nM. In vitro endonuclease cleavage assay with RNA substrates, binding constant (Kd) determination, size exclusion chromatography, mutagenesis of active site (D141N) Scientific reports High 29743536
2019 Regnase-1 directly targets Tcf7 (TCF-1) mRNA for degradation; its deficiency in CD8+ T cells augments TCF-1 expression, promoting formation of TCF-1+ precursor exhausted T cells with improved persistence and antitumor efficacy. Regnase-1 KO (CRISPR), mRNA stability assay for Tcf7, CRISPR genome-scale screen identifying BATF as key downstream target Nature High 31827283
2021 Roquin-1 physically interacts with Regnase-1 via a defined interaction surface that includes the sanroque residue; mutations in Roquin-1 disrupting this interaction impair cooperative target mRNA repression and induce autoimmunity. Co-IP of Roquin-1/Regnase-1, interaction surface mutagenesis, T cell phenotyping in knockin mice Nature immunology High 34811541
2021 In IL-33- and IL-25-stimulated ILC2s, IκB kinase (IKK) complex-mediated phosphorylation of Regnase-1 at S435/S439 is required for its degradation and ILC2 activation; a phosphorylation-resistant S435A/S439A Regnase-1 mutant prevents ILC2 proliferation and type 2 cytokine production; Il2ra and Il1rl1 mRNAs are direct Regnase-1 targets in ILC2s. Regnase-1 phospho-mutant knockin mice, ILC2 stimulation assays, mRNA stability assays, cytokine measurement JCI insight High 31990689
2018 In the context of the NFKBIZ 3'-UTR translational silencing element (TSE), MCPIP1 suppresses translation in addition to promoting mRNA degradation; MCPIP1 depletion increases polysomal association of the mRNA; this translational silencing requires SL1-3 of the TSE beyond the SL4-5 required for mRNA destabilization, indicating context-dependent functional diversification. MCPIP1 overexpression/knockdown, ribosome profiling/polysome analysis, reporter assays with TSE mutants, IRES-dependent translation assay Nucleic acids research Medium 29471506
2017 MCPIP1 binds and cleaves C/EBPβ mRNA via regions of its 3'-UTR through direct endonucleolytic cleavage, demonstrated by in vitro cleavage assay, luciferase-reporter assay, and RNA immunoprecipitation. In vitro cleavage assay, luciferase 3'-UTR reporter assay, RNA immunoprecipitation (RIP) PloS one Medium 28328949
2013 MCPIP1 restricts HIV-1 production via its RNase domain by decreasing steady-state viral mRNA levels; proteasomal degradation of MCPIP1 upon T cell activation removes this restriction, explaining why activated CD4+ T cells support HIV-1 replication. MCPIP1 overexpression/KD in T cell lines and primary CD4+ T cells, HIV-1 replication assays, proteasome inhibitor (MG132) treatment Proceedings of the National Academy of Sciences of the United States of America Medium 24191027
2011 MCPIP1 overexpression suppresses stress granule (SG) assembly and sensitizes cells to stress-induced apoptosis; this SG repression depends on MCPIP1's deubiquitinating activity, and MCPIP1 negatively regulates stress-induced eIF2α phosphorylation to relieve inhibition of protein translation. MCPIP1 overexpression/KO, SG imaging, mutagenesis (deubiquitinase domain), eIF2α phosphorylation assay, apoptosis assay The Journal of biological chemistry Medium 21971051
2015 MCPIP1 endoribonuclease activity is required for feedback inhibition of IL-17 receptor signaling; MCPIP1 degrades Il6 mRNA directly and degrades Il17ra/Il17rc mRNA independently of the 3'-UTR, and also degrades Nfkbiz mRNA to suppress IκBζ-driven transcription. MCPIP1 knockdown (RNase-dead mutant analysis), mRNA decay assays, haploinsufficient and IL-17RA KO epistasis, in vivo models Immunity High 26320658
2021 TUT7 (terminal uridyltransferase 7) directly binds to the stem-loop structure in the Zc3h12a 3'-UTR after TLR4 activation, promotes uridylation of Regnase-1 mRNA, and thereby destabilizes Regnase-1 mRNA; Zc3h12a from LPS-treated TUT7-sufficient macrophages has increased oligo-uridylated ends with shorter poly(A) tails, which is substantially reduced in Tut7−/− cells. TUT7 KO mice, RNA 3' end sequencing, direct RNA binding assay (TUT7 to Zc3h12a 3'-UTR stem-loop), mRNA stability assay Nature communications High 34188032
2015 IL-17 stabilizes Zc3h12a mRNA by promoting formation of a CIKS-DDX3X complex; DDX3X directly binds Zc3h12a mRNA after IL-17 stimulation, and this stabilization requires the helicase domain of DDX3X (but not ATPase activity) and also requires IKKε, TRAF2, and TRAF5. Co-IP (CIKS-DDX3X), DDX3X knockdown, RNA immunoprecipitation (RIP), mRNA half-life assay, domain mutant analysis Journal of immunology Medium 25710910
2010 IL-1β-induced transcription of ZC3H12A is mediated through the MAP kinase pathway and the transcription factors Elk-1 and SRF, which bind a promoter region from -76 to +60 as confirmed by chromatin immunoprecipitation. Promoter reporter assay, signaling pathway inhibitors, chromatin immunoprecipitation (ChIP) for Elk-1 and SRF BMC molecular biology Medium 20137095
2019 Regnase-1 regulates hematopoietic stem and progenitor cell (HSPC) self-renewal by degrading Gata2 and Tal1 mRNAs; Regnase-1 deficiency in HSPCs leads to rapid onset of abnormal hematopoiesis. Conditional KO of Regnase-1 in HSPCs, mRNA stability assays for Gata2 and Tal1, HSPC functional assays Nature communications Medium 30842549
2022 Antisense morpholino oligonucleotides (MOs) targeting the stem-loop structure in the Regnase-1 3'-UTR block Regnase-1 self-regulatory mRNA degradation, enhancing Regnase-1 protein abundance and thereby reducing expression of Regnase-1 target inflammatory transcripts; this demonstrates that Regnase-1 degrades its own mRNA via recognition of stem-loop structures in its 3'-UTR. Antisense MO treatment, Regnase-1 mRNA stability assay, target mRNA expression analysis in macrophages and in vivo models Science translational medicine High 35544597
2024 Regnase-1 deletion in NK cells augments antitumor IFN-γ production by increasing expression of the transcriptional regulators OCT2 and IκBζ; the resulting OCT2-IκBζ-NF-κB complex drives Ifng transcription. Regnase-1 directly targets mRNAs for OCT2 (POU2F2) and IκBζ. NK cell-specific Regnase-1 KO, transcriptional profiling, OCT2/IκBζ target validation, complex formation (Co-IP), in vivo tumor models Immunity High 38821052
2014 MCPIP1 suppresses HCV replication by directly binding HCV RNA and degrading it via its RNase activity; RNA binding, oligomerization, and RNase activity are required, but deubiquitinase activity is not; in vitro RNA cleavage assay with replication-defective HCV demonstrated direct degradation of HCV RNA by MCPIP1. MCPIP1 overexpression/KD, domain mutant analysis, in vitro RNA cleavage assay, RNA immunoprecipitation Journal of immunology High 25225661
2021 MCPIP1 RNase activity degrades mRNAs encoding anti-apoptotic proteins BCL3, BCL2A1, BCL2L1, and MCL-1, promoting spontaneous apoptosis of primary neutrophils; loss of MCPIP1 in neutrophils prolongs their survival. Cell-specific MCPIP1 KO in neutrophils, mRNA stability assays for anti-apoptotic transcripts, apoptosis assays Frontiers in immunology Medium 33717148
2022 Macrophage-specific MCPIP1 deficiency arrests monocyte-to-macrophage maturation in the gut in an ATF3-AP1S2 axis-dependent manner, promoting proinflammatory M1-like polarization; scRNA-seq plus CUT&Tag and luciferase assays confirmed that MCPIP1 controls ATF3, which in turn regulates AP1S2 expression. Macrophage-specific Mcpip1 KO mice, scRNA-seq, RNA-seq, CUT&Tag, luciferase assay, in vivo AP1S2 blockage Gut High 37015751
2021 Regnase-1 deficiency in ILC2s leads to spontaneous ILC2 proliferation/activation in the lung; Regnase-1 suppresses mRNAs encoding the transcription factors Gata3 and Egr1, which regulate fibrosis-associated genes, thereby controlling ILC2 profibrotic function. Competitive bone marrow transfer, ILC2-specific Regnase-1 deficiency, mRNA stability assays for Gata3 and Egr1, bleomycin pulmonary fibrosis model The European respiratory journal Medium 32978308
2018 Regnase-1 controls colon epithelial regeneration by regulating mTORC1 signaling and purine metabolism; intestinal epithelial cell-specific Regnase-1 deletion increases cell proliferation and decreases apoptosis during DSS-induced injury, and Regnase-1 primarily regulates mTORC1 signaling pathway in epithelial cells. IEC-specific Regnase-1 KO mice, DSS colitis model, metabolomic analysis, mTOR pathway analysis Proceedings of the National Academy of Sciences of the United States of America Medium 30297433
2016 MCPIP1 possesses RNase activity toward IL-8 mRNA; the stability of IL-8 mRNA is controlled by stem-loop/hairpin structures in the IL-8 3'-UTR that MCPIP1 recognizes and cleaves, as demonstrated with purified recombinant MCPIP1 protein in an in vitro cleavage assay. In vitro cleavage assay with purified recombinant MCPIP1, 3'-UTR reporter assay for IL-8, siRNA knockdown Journal of innate immunity Medium 27513529
2019 RGS2 protein is stabilized by MCPIP1 deubiquitinase activity; the dominant-negative C157A MCPIP1 mutant (deubiquitinase-dead) does not stabilize RGS2, indicating that MCPIP1's deubiquitinase domain is required for this function. Co-expression of MCPIP1 and RGS2, C157A mutant analysis, proteasome inhibitor (MG132) treatment Journal of cellular biochemistry Low 25187114
2021 MCPIP1 inhibits the Wnt/β-catenin pathway and EMT in ccRCC by degrading miRNAs (miR-519a-3p, miR-519b-3p, miR-520c-3p) via its RNase activity, thus protecting mRNAs of Wnt pathway inhibitors (SFRP4, KREMEN1, CXXC4, CSNK1A1, ZNFR3) from miRNA-mediated degradation. RNase-activity-dependent miRNA profiling, mRNA stability assays, MCPIP1 overexpression/RNase-dead mutant in ccRCC cell lines and xenografts Oncogene Medium 34657130
2017 Regnase-1 and Roquin synergistically control Th1 polarization by repressing mRNAs of Furin and Il12rb1 via their 3'-UTRs; additionally, Regnase-1 represses Roquin mRNA, establishing cross-regulation between these two proteins. T cell-conditional Regnase-1/Roquin single and double KO mice, mRNA stability assays, 3'-UTR reporter assays Journal of immunology Medium 29127149

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 577 19322177
2019 Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 359 31827283
2015 Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms. Cell 321 26000482
2013 Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell 293 23706741
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
2015 MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation. Immunity 130 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 97 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 Monocyte chemotactic protein-1-induced protein-1 (MCPIP1) is a novel multifunctional modulator of inflammatory reactions. Biochimica et biophysica acta 77 22771441
2021 Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood 76 33690816
2017 MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression. Cancer research 76 28716897
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
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
2017 MCPIP1 contributes to clear cell renal cell carcinomas development. Angiogenesis 67 28197812
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
2017 Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses. Cellular & molecular immunology 65 28194024
2022 MCPIP1 restrains mucosal inflammation by orchestrating the intestinal monocyte to macrophage maturation via an ATF3-AP1S2 axis. Gut 64 37015751
2010 Transcription factors Elk-1 and SRF are engaged in IL1-dependent regulation of ZC3H12A expression. BMC molecular biology 64 20137095
2022 Regnase-1 Prevents Pulmonary Arterial Hypertension Through mRNA Degradation of Interleukin-6 and Platelet-Derived Growth Factor in Alveolar Macrophages. Circulation 62 35997026
2017 Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs. Cell reports 59 28538180
2017 Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury. Signal transduction and targeted therapy 58 29263935
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 55 31072819
2015 RGS2 suppresses breast cancer cell growth via a MCPIP1-dependent pathway. Journal of cellular biochemistry 52 25187114
2019 Translation-dependent unwinding of stem-loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs. Nucleic acids research 51 31329944
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
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
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 40 26865670
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
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
2022 Resistance to tyrosine kinase inhibitors promotes renal cancer progression through MCPIP1 tumor-suppressor downregulation and c-Met activation. Cell death & disease 34 36138026
2019 MiR-421 promotes the development of osteosarcoma by regulating MCPIP1 expression. Cancer biology & therapy 34 31718519
2019 MCP-1 mediates ischemia-reperfusion-induced cardiomyocyte apoptosis via MCPIP1 and CaSR. American journal of physiology. Heart and circulatory physiology 34 31774703
2021 MCPIP1 inhibits Wnt/β-catenin signaling pathway activity and modulates epithelial-mesenchymal transition during clear cell renal cell carcinoma progression by targeting miRNAs. Oncogene 33 34657130
2016 Modulation of influenza A virus replication by microRNA-9 through targeting MCPIP1. Journal of medical virology 33 27322373
2013 Regnase-1, a ribonuclease involved in the regulation of immune responses. Cold Spring Harbor symposia on quantitative biology 33 24163394
2016 Virus-Mediated Alterations in miRNA Factors and Degradation of Viral miRNAs by MCPIP1. PLoS biology 32 27893764
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
2021 MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis. Cell death & disease 29 33824311
2015 MCPIP1 mediates silica-induced cell migration in human pulmonary fibroblasts. American journal of physiology. Lung cellular and molecular physiology 29 26608530
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
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
2022 Enhancement of Regnase-1 expression with stem loop-targeting antisense oligonucleotides alleviates inflammatory diseases. Science translational medicine 22 35544597
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
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
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 Deletion of Mcpip1 in Mcpip1fl/flAlbCre mice recapitulates the phenotype of human primary biliary cholangitis. Biochimica et biophysica acta. Molecular basis of disease 18 33513427
2021 MCPIP-1 Restricts Inflammation via Promoting Apoptosis of Neutrophils. Frontiers in immunology 18 33717148
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
2021 Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation. Disease models & mechanisms 17 33737335
2021 Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation. Frontiers in immunology 17 34659213
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
2018 MCPIP1-induced autophagy mediates ischemia/reperfusion injury in endothelial cells via HMGB1 and CaSR. Scientific reports 16 29379093
2017 MCPIP1 contributes to the inflammatory response of UVB-treated keratinocytes. Journal of dermatological science 16 28377026
2017 Ectopic overexpression of MCPIP1 impairs adipogenesis by modulating microRNAs. Biochimica et biophysica acta. Molecular cell research 16 28939056
2024 Suppression of TCF4 promotes a ZC3H12A-mediated self-sustaining inflammatory feedback cycle involving IL-17RA/IL-17RE epidermal signaling. JCI insight 15 38470486
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 15 37126984
2022 Macrophage-Specific MCPIP1/Regnase-1 Attenuates Kidney Ischemia-Reperfusion Injury by Shaping the Local Inflammatory Response and Tissue Regeneration. Cells 15 35159206
2021 MCPIP1 Enhances TNF-α-Mediated Apoptosis through Downregulation of the NF-κB/cFLIP Axis. Biology 15 34356509
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
2019 MCPIP1 regulates the sensitivity of pancreatic beta-cells to cytokine toxicity. Cell death & disease 15 30631045
2011 Post-transcriptional regulation of IL-6 production by Zc3h12a in fibroblast-like synovial cells. Clinical and experimental rheumatology 15 22132693
2021 IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay. eLife 14 34636324
2019 The role of monocyte chemotactic protein-induced protein 1 (MCPIP1) in angiotensin II-induced macrophage apoptosis and vulnerable plaque formation. Biochemical and biophysical research communications 14 31155290
2019 Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism. Cellular and molecular life sciences : CMLS 14 31893310
2013 MCPIP1 deficiency in mice results in severe anemia related to autoimmune mechanisms. PloS one 14 24324805

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