{"gene":"ZC3H12A","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2009,"finding":"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.","method":"Overexpression/knockout in macrophages, mRNA stability assays, 3'-UTR reporter assays, RNase activity assay on purified protein","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro RNase activity assay plus genetic KO with defined mRNA decay phenotype, foundational paper replicated by many subsequent studies","pmids":["19322177"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-IP, cleavage assay, mutagenesis of cleavage site (R111), T cell-specific conditional KO, mRNA stability assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — identified cleavage site by mutagenesis, in vitro cleavage confirmed, replicated by independent lab (PMID:25282160)","pmids":["23706741"],"is_preprint":false},{"year":2014,"finding":"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.","method":"MALT1 cleavage assays, nuclease-dead Regnase-1 mutant, mRNA stability reporter assays, T cell differentiation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cleavage confirmed with mutagenesis, cooperative mechanism demonstrated orthogonally, independent replication of MALT1-Regnase-1 axis","pmids":["25282160"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Subcellular fractionation, ribosome profiling, UPF1 knockdown, live imaging, co-IP, mRNA decay assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (fractionation, ribosome profiling, UPF1 KD), replicated in subsequent studies","pmids":["26000482"],"is_preprint":false},{"year":2011,"finding":"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.","method":"In vitro pre-miRNA cleavage assay, mutagenesis of RNase domain, overexpression/knockdown in mammalian cells, miRNA profiling","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage assay with domain mutagenesis, single lab with multiple orthogonal methods","pmids":["22055188"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-IP (MCPIP1-NEMO-USP10 interaction), ubiquitin chain analysis, NF-κB reporter assays, USP10 KD epistasis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus epistasis analysis in single lab, two orthogonal methods","pmids":["24270572"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Viral RNA cleavage assay, MCPIP1 overexpression/knockdown in virus-infected cells, domain mutant analysis (RNase-dead, oligomerization-deficient)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro RNA cleavage assay plus systematic domain mutagenesis in single lab","pmids":["23355615"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Phosphorylation mapping, CRISPR/Cas9 knockin of phospho-deficient Regnase-1 mutant mice, subcellular fractionation, IL-17 response assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR knockin phospho-mutant mice combined with fractionation and functional rescue, multiple orthogonal methods","pmids":["31072819"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Regnase-1 KO mice, mRNA stability assay for TfR1 and PHD3, iron metabolism phenotyping, transcriptome analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype and mRNA targets, multiple pathways validated in vivo","pmids":["28538180"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Single-molecule imaging, co-IP, domain mutagenesis, SMG1 inhibitor treatment, dendritic cell mRNA decay assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — single-molecule imaging plus co-IP interaction mapping and small-molecule inhibition, multiple orthogonal methods","pmids":["31329944"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Regnase-1 interactome analysis (MS), Co-IP, phospho-site mutagenesis, mRNA decay assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — interactome MS plus Co-IP plus phospho-mutagenesis plus functional mRNA decay assays","pmids":["34636324"],"is_preprint":false},{"year":2018,"finding":"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.","method":"In vitro endonuclease cleavage assay with RNA substrates, binding constant (Kd) determination, size exclusion chromatography, mutagenesis of active site (D141N)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic in vitro biochemistry with purified protein, multiple RNA substrates, and mutagenesis","pmids":["29743536"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Regnase-1 KO (CRISPR), mRNA stability assay for Tcf7, CRISPR genome-scale screen identifying BATF as key downstream target","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO with mRNA target validation plus genome-scale epistasis screen identifying downstream pathway","pmids":["31827283"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-IP of Roquin-1/Regnase-1, interaction surface mutagenesis, T cell phenotyping in knockin mice","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with mutagenesis of interaction surface plus in vivo functional validation","pmids":["34811541"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Regnase-1 phospho-mutant knockin mice, ILC2 stimulation assays, mRNA stability assays, cytokine measurement","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phospho-mutant knockin with defined mRNA targets and functional ILC2 phenotype","pmids":["31990689"],"is_preprint":false},{"year":2018,"finding":"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.","method":"MCPIP1 overexpression/knockdown, ribosome profiling/polysome analysis, reporter assays with TSE mutants, IRES-dependent translation assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polysome profiling plus systematic TSE mutagenesis in single lab","pmids":["29471506"],"is_preprint":false},{"year":2017,"finding":"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.","method":"In vitro cleavage assay, luciferase 3'-UTR reporter assay, RNA immunoprecipitation (RIP)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro cleavage confirmed but single lab, limited functional follow-up","pmids":["28328949"],"is_preprint":false},{"year":2013,"finding":"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.","method":"MCPIP1 overexpression/KD in T cell lines and primary CD4+ T cells, HIV-1 replication assays, proteasome inhibitor (MG132) treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNase-domain-dependent mechanism in primary T cells plus proteasomal degradation confirmed, single lab","pmids":["24191027"],"is_preprint":false},{"year":2011,"finding":"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.","method":"MCPIP1 overexpression/KO, SG imaging, mutagenesis (deubiquitinase domain), eIF2α phosphorylation assay, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis identifies specific domain requirement plus eIF2α phosphorylation mechanistic link, single lab","pmids":["21971051"],"is_preprint":false},{"year":2015,"finding":"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.","method":"MCPIP1 knockdown (RNase-dead mutant analysis), mRNA decay assays, haploinsufficient and IL-17RA KO epistasis, in vivo models","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — RNase-dead mutant epistasis plus multiple mRNA substrate validation plus in vivo genetic epistasis","pmids":["26320658"],"is_preprint":false},{"year":2021,"finding":"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.","method":"TUT7 KO mice, RNA 3' end sequencing, direct RNA binding assay (TUT7 to Zc3h12a 3'-UTR stem-loop), mRNA stability assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — KO mice plus direct RNA binding plus 3'-end sequencing mechanistically linking TUT7 to Regnase-1 mRNA turnover","pmids":["34188032"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-IP (CIKS-DDX3X), DDX3X knockdown, RNA immunoprecipitation (RIP), mRNA half-life assay, domain mutant analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus Co-IP plus domain mutagenesis in single lab","pmids":["25710910"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Promoter reporter assay, signaling pathway inhibitors, chromatin immunoprecipitation (ChIP) for Elk-1 and SRF","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms in vivo binding plus reporter assay, single lab","pmids":["20137095"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Conditional KO of Regnase-1 in HSPCs, mRNA stability assays for Gata2 and Tal1, HSPC functional assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined mRNA targets, single lab","pmids":["30842549"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Antisense MO treatment, Regnase-1 mRNA stability assay, target mRNA expression analysis in macrophages and in vivo models","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic demonstration of Regnase-1 self-regulation via 3'-UTR stem-loop with both in vitro and in vivo validation","pmids":["35544597"],"is_preprint":false},{"year":2024,"finding":"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.","method":"NK cell-specific Regnase-1 KO, transcriptional profiling, OCT2/IκBζ target validation, complex formation (Co-IP), in vivo tumor models","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — NK cell-specific KO plus Co-IP complex identification plus mRNA target validation in vivo and in human NK cells","pmids":["38821052"],"is_preprint":false},{"year":2014,"finding":"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.","method":"MCPIP1 overexpression/KD, domain mutant analysis, in vitro RNA cleavage assay, RNA immunoprecipitation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro RNA cleavage assay plus domain mutagenesis plus RIP in single lab","pmids":["25225661"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Cell-specific MCPIP1 KO in neutrophils, mRNA stability assays for anti-apoptotic transcripts, apoptosis assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined mRNA target validation, single lab","pmids":["33717148"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Macrophage-specific Mcpip1 KO mice, scRNA-seq, RNA-seq, CUT&Tag, luciferase assay, in vivo AP1S2 blockage","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with scRNA-seq pathway dissection and multiple orthogonal methods in single lab","pmids":["37015751"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Competitive bone marrow transfer, ILC2-specific Regnase-1 deficiency, mRNA stability assays for Gata3 and Egr1, bleomycin pulmonary fibrosis model","journal":"The European respiratory journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined mRNA targets with in vivo functional consequences, single lab","pmids":["32978308"],"is_preprint":false},{"year":2018,"finding":"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.","method":"IEC-specific Regnase-1 KO mice, DSS colitis model, metabolomic analysis, mTOR pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype and metabolic analysis, single lab","pmids":["30297433"],"is_preprint":false},{"year":2016,"finding":"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.","method":"In vitro cleavage assay with purified recombinant MCPIP1, 3'-UTR reporter assay for IL-8, siRNA knockdown","journal":"Journal of innate immunity","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro cleavage with purified protein but single lab, limited mechanistic follow-up","pmids":["27513529"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-expression of MCPIP1 and RGS2, C157A mutant analysis, proteasome inhibitor (MG132) treatment","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/overexpression approach, domain mutant supports mechanism, but limited biochemical validation","pmids":["25187114"],"is_preprint":false},{"year":2021,"finding":"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.","method":"RNase-activity-dependent miRNA profiling, mRNA stability assays, MCPIP1 overexpression/RNase-dead mutant in ccRCC cell lines and xenografts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNase-dead mutant plus miRNA and mRNA target validation, single lab","pmids":["34657130"],"is_preprint":false},{"year":2017,"finding":"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.","method":"T cell-conditional Regnase-1/Roquin single and double KO mice, mRNA stability assays, 3'-UTR reporter assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional double KO with defined mRNA targets and cross-regulation, single lab","pmids":["29127149"],"is_preprint":false}],"current_model":"ZC3H12A/MCPIP1/Regnase-1 is an endoribonuclease that degrades a specific set of inflammatory, immune-regulatory, and metabolic mRNAs by recognizing and cleaving stem-loop structures in their 3'-UTRs in a translation- and UPF1-dependent manner at the ribosome/ER; it also suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops, can deubiquitinate substrates via a separate domain, and is itself post-translationally regulated by IKK- and IRAK1-mediated phosphorylation (leading to proteasomal degradation or 14-3-3-mediated sequestration) and by MALT1-mediated proteolytic cleavage upon TCR activation, collectively making it a central hub for resolving inflammation and maintaining immune homeostasis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2009,"claim":"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","pmids":["19322177"],"confidence":"High","gaps":["3'-UTR sequence/structure determinant of substrate selection not yet defined","structural basis of catalysis not resolved"]},{"year":2011,"claim":"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","pmids":["22055188"],"confidence":"High","gaps":["physiological scope of miRNA regulation in vivo unclear","selectivity between pre-miRNA and mRNA substrates undefined"]},{"year":2010,"claim":"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","pmids":["20137095"],"confidence":"Medium","gaps":["additional transcriptional inputs not mapped","link between induction kinetics and inflammatory resolution untested"]},{"year":2013,"claim":"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","pmids":["24270572","23355615","24191027","23706741"],"confidence":"High","gaps":["whether ZC3H12A has intrinsic deubiquitinase catalysis vs. adaptor role unresolved","in vivo significance of antiviral RNA degradation versus mRNA decay not separated"]},{"year":2015,"claim":"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","pmids":["26000482","26320658"],"confidence":"High","gaps":["mechanism coupling translation status to cleavage not yet biochemically reconstituted","how 3'-UTR-independent Il17ra/Il17rc degradation occurs unexplained"]},{"year":2018,"claim":"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","pmids":["29743536","29471506"],"confidence":"High","gaps":["high-resolution structure of enzyme-RNA complex not determined","how decay versus translational silencing is selected on the same transcript unclear"]},{"year":2017,"claim":"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","pmids":["28538180","28328949","27513529"],"confidence":"Medium","gaps":["tissue-specific target hierarchy not defined","some target validations rest on single-lab in vitro cleavage"]},{"year":2019,"claim":"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","pmids":["31329944","31072819","34636324","30842549","31827283"],"confidence":"High","gaps":["integration of competing phospho-signals in vivo not quantitatively modeled","cross-talk between localization control and substrate choice incompletely defined"]},{"year":2021,"claim":"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","pmids":["34188032","25710910","34811541","31990689","33717148","34657130"],"confidence":"High","gaps":["relative contribution of mRNA uridylation versus self-cleavage to Regnase-1 turnover unresolved","structural detail of the Roquin-Regnase-1 complex absent"]},{"year":2024,"claim":"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","pmids":["38821052","37015751"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["no atomic structure of the catalytically engaged enzyme-RNA-UPF1 complex","quantitative integration of competing regulatory inputs lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,4,6,11,26,31]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,11,16,26]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,18,32]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,18]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,19,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,10]}],"complexes":[],"partners":["UPF1","ROQUIN/RC3H1","MALT1","USP10","NEMO/IKBKG","14-3-3","DDX3X","TUT7/ZCCHC6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5D1E8","full_name":"Endoribonuclease ZC3H12A","aliases":["Monocyte chemotactic protein-induced protein 1","MCP-induced protein 1","MCPIP-1","Regnase-1","Reg1","Zinc finger CCCH domain-containing protein 12A"],"length_aa":599,"mass_kda":65.7,"function":"Endoribonuclease involved in various biological functions such as cellular inflammatory response and immune homeostasis, glial differentiation of neuroprogenitor cells, cell death of cardiomyocytes, adipogenesis and angiogenesis. Functions as an endoribonuclease involved in mRNA decay (PubMed:19909337). Modulates the inflammatory response by promoting the degradation of a set of translationally active cytokine-induced inflammation-related mRNAs, such as IL6 and IL12B, during the early phase of inflammation (PubMed:26320658). Prevents aberrant T-cell-mediated immune reaction by degradation of multiple mRNAs controlling T-cell activation, such as those encoding cytokines (IL6 and IL2), cell surface receptors (ICOS, TNFRSF4 and TNFR2) and transcription factor (REL) (By similarity). Inhibits cooperatively with ZC3H12A the differentiation of helper T cells Th17 in lungs. They repress target mRNA encoding the Th17 cell-promoting factors IL6, ICOS, REL, IRF4, NFKBID and NFKBIZ. The cooperation requires RNA-binding by RC3H1 and the nuclease activity of ZC3H12A (By similarity). Together with RC3H1, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR (By similarity). Self regulates by destabilizing its own mRNA (By similarity). Cleaves mRNA harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-dependent manner (PubMed:19909337, PubMed:22561375, PubMed:26134560, PubMed:26320658). Plays a role in the inhibition of microRNAs (miRNAs) biogenesis (PubMed:22055188). Cleaves the terminal loop of a set of precursor miRNAs (pre-miRNAs) important for the regulation of the inflammatory response leading to their degradation, and thus preventing the biosynthesis of mature miRNAs (PubMed:22055188). Also plays a role in promoting angiogenesis in response to inflammatory cytokines by inhibiting the production of antiangiogenic microRNAs via its anti-dicer RNase activity (PubMed:24048733). Affects the overall ubiquitination of cellular proteins (By similarity). Positively regulates deubiquitinase activity promoting the cleavage at 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains on TNF receptor-associated factors (TRAFs), preventing JNK and NF-kappa-B signaling pathway activation, and hence negatively regulating macrophage-mediated inflammatory response and immune homeostasis (By similarity). Also induces deubiquitination of the transcription factor HIF1A, probably leading to its stabilization and nuclear import, thereby positively regulating the expression of proangiogenic HIF1A-targeted genes (PubMed:24048733). Involved in a TANK-dependent negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Prevents stress granule (SGs) formation and promotes macrophage apoptosis under stress conditions, including arsenite-induced oxidative stress, heat shock and energy deprivation (By similarity). Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state (By similarity). May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis (PubMed:16574901, PubMed:18364357). Functions as a positive regulator of glial differentiation of neuroprogenitor cells through an amyloid precursor protein (APP)-dependent signaling pathway (PubMed:19185603). Attenuates septic myocardial contractile dysfunction in response to lipopolysaccharide (LPS) by reducing I-kappa-B-kinase (IKK)-mediated NF-kappa-B activation, and hence myocardial pro-inflammatory cytokine production (By similarity) (Microbial infection) Binds to Japanese encephalitis virus (JEV) and Dengue virus (DEN) RNAs (Microbial infection) Exhibits antiviral activity against HIV-1 in lymphocytes by decreasing the abundance of HIV-1 viral RNA species","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, P-body; Rough endoplasmic reticulum membrane; Cytoplasmic granule","url":"https://www.uniprot.org/uniprotkb/Q5D1E8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZC3H12A","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZC3H12A","total_profiled":1310},"omim":[{"mim_id":"615001","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 12C; ZC3H12C","url":"https://www.omim.org/entry/615001"},{"mim_id":"611583","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 5A; ARID5A","url":"https://www.omim.org/entry/611583"},{"mim_id":"611106","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 12D; ZC3H12D","url":"https://www.omim.org/entry/611106"},{"mim_id":"610562","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 12A; ZC3H12A","url":"https://www.omim.org/entry/610562"},{"mim_id":"609532","title":"HEPATITIS C VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609532"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytoplasmic bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":128.7}],"url":"https://www.proteinatlas.org/search/ZC3H12A"},"hgnc":{"alias_symbol":["FLJ23231","MCPIP1","Regnase-1"],"prev_symbol":[]},"alphafold":{"accession":"Q5D1E8","domains":[{"cath_id":"3.40.50.11980","chopping":"139-301","consensus_level":"high","plddt":95.4962,"start":139,"end":301},{"cath_id":"1.10.8","chopping":"45-90","consensus_level":"high","plddt":87.4835,"start":45,"end":90},{"cath_id":"1.10.8","chopping":"551-596","consensus_level":"high","plddt":90.7926,"start":551,"end":596}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5D1E8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5D1E8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5D1E8-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZC3H12A","jax_strain_url":"https://www.jax.org/strain/search?query=ZC3H12A"},"sequence":{"accession":"Q5D1E8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5D1E8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5D1E8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5D1E8"}},"corpus_meta":[{"pmid":"19322177","id":"PMC_19322177","title":"Zc3h12a 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expressed protein showed RNase activity and accelerated Il6 mRNA degradation in a 3'-UTR-dependent manner in macrophages.\",\n      \"method\": \"Overexpression/knockout in macrophages, mRNA stability assays, 3'-UTR reporter assays, RNase activity assay on purified protein\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro RNase activity assay plus genetic KO with defined mRNA decay phenotype, foundational paper replicated by many subsequent studies\",\n      \"pmids\": [\"19322177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, cleavage assay, mutagenesis of cleavage site (R111), T cell-specific conditional KO, mRNA stability assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — identified cleavage site by mutagenesis, in vitro cleavage confirmed, replicated by independent lab (PMID:25282160)\",\n      \"pmids\": [\"23706741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"MALT1 cleavage assays, nuclease-dead Regnase-1 mutant, mRNA stability reporter assays, T cell differentiation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cleavage confirmed with mutagenesis, cooperative mechanism demonstrated orthogonally, independent replication of MALT1-Regnase-1 axis\",\n      \"pmids\": [\"25282160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, ribosome profiling, UPF1 knockdown, live imaging, co-IP, mRNA decay assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (fractionation, ribosome profiling, UPF1 KD), replicated in subsequent studies\",\n      \"pmids\": [\"26000482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro pre-miRNA cleavage assay, mutagenesis of RNase domain, overexpression/knockdown in mammalian cells, miRNA profiling\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage assay with domain mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22055188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP (MCPIP1-NEMO-USP10 interaction), ubiquitin chain analysis, NF-κB reporter assays, USP10 KD epistasis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus epistasis analysis in single lab, two orthogonal methods\",\n      \"pmids\": [\"24270572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Viral RNA cleavage assay, MCPIP1 overexpression/knockdown in virus-infected cells, domain mutant analysis (RNase-dead, oligomerization-deficient)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro RNA cleavage assay plus systematic domain mutagenesis in single lab\",\n      \"pmids\": [\"23355615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorylation mapping, CRISPR/Cas9 knockin of phospho-deficient Regnase-1 mutant mice, subcellular fractionation, IL-17 response assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR knockin phospho-mutant mice combined with fractionation and functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"31072819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Regnase-1 KO mice, mRNA stability assay for TfR1 and PHD3, iron metabolism phenotyping, transcriptome analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype and mRNA targets, multiple pathways validated in vivo\",\n      \"pmids\": [\"28538180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Single-molecule imaging, co-IP, domain mutagenesis, SMG1 inhibitor treatment, dendritic cell mRNA decay assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — single-molecule imaging plus co-IP interaction mapping and small-molecule inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"31329944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Regnase-1 interactome analysis (MS), Co-IP, phospho-site mutagenesis, mRNA decay assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — interactome MS plus Co-IP plus phospho-mutagenesis plus functional mRNA decay assays\",\n      \"pmids\": [\"34636324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro endonuclease cleavage assay with RNA substrates, binding constant (Kd) determination, size exclusion chromatography, mutagenesis of active site (D141N)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic in vitro biochemistry with purified protein, multiple RNA substrates, and mutagenesis\",\n      \"pmids\": [\"29743536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Regnase-1 KO (CRISPR), mRNA stability assay for Tcf7, CRISPR genome-scale screen identifying BATF as key downstream target\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO with mRNA target validation plus genome-scale epistasis screen identifying downstream pathway\",\n      \"pmids\": [\"31827283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of Roquin-1/Regnase-1, interaction surface mutagenesis, T cell phenotyping in knockin mice\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with mutagenesis of interaction surface plus in vivo functional validation\",\n      \"pmids\": [\"34811541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Regnase-1 phospho-mutant knockin mice, ILC2 stimulation assays, mRNA stability assays, cytokine measurement\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phospho-mutant knockin with defined mRNA targets and functional ILC2 phenotype\",\n      \"pmids\": [\"31990689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"MCPIP1 overexpression/knockdown, ribosome profiling/polysome analysis, reporter assays with TSE mutants, IRES-dependent translation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome profiling plus systematic TSE mutagenesis in single lab\",\n      \"pmids\": [\"29471506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assay, luciferase 3'-UTR reporter assay, RNA immunoprecipitation (RIP)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro cleavage confirmed but single lab, limited functional follow-up\",\n      \"pmids\": [\"28328949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"MCPIP1 overexpression/KD in T cell lines and primary CD4+ T cells, HIV-1 replication assays, proteasome inhibitor (MG132) treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNase-domain-dependent mechanism in primary T cells plus proteasomal degradation confirmed, single lab\",\n      \"pmids\": [\"24191027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"MCPIP1 overexpression/KO, SG imaging, mutagenesis (deubiquitinase domain), eIF2α phosphorylation assay, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis identifies specific domain requirement plus eIF2α phosphorylation mechanistic link, single lab\",\n      \"pmids\": [\"21971051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"MCPIP1 knockdown (RNase-dead mutant analysis), mRNA decay assays, haploinsufficient and IL-17RA KO epistasis, in vivo models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — RNase-dead mutant epistasis plus multiple mRNA substrate validation plus in vivo genetic epistasis\",\n      \"pmids\": [\"26320658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"TUT7 KO mice, RNA 3' end sequencing, direct RNA binding assay (TUT7 to Zc3h12a 3'-UTR stem-loop), mRNA stability assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — KO mice plus direct RNA binding plus 3'-end sequencing mechanistically linking TUT7 to Regnase-1 mRNA turnover\",\n      \"pmids\": [\"34188032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP (CIKS-DDX3X), DDX3X knockdown, RNA immunoprecipitation (RIP), mRNA half-life assay, domain mutant analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus Co-IP plus domain mutagenesis in single lab\",\n      \"pmids\": [\"25710910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Promoter reporter assay, signaling pathway inhibitors, chromatin immunoprecipitation (ChIP) for Elk-1 and SRF\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms in vivo binding plus reporter assay, single lab\",\n      \"pmids\": [\"20137095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional KO of Regnase-1 in HSPCs, mRNA stability assays for Gata2 and Tal1, HSPC functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined mRNA targets, single lab\",\n      \"pmids\": [\"30842549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Antisense MO treatment, Regnase-1 mRNA stability assay, target mRNA expression analysis in macrophages and in vivo models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic demonstration of Regnase-1 self-regulation via 3'-UTR stem-loop with both in vitro and in vivo validation\",\n      \"pmids\": [\"35544597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"NK cell-specific Regnase-1 KO, transcriptional profiling, OCT2/IκBζ target validation, complex formation (Co-IP), in vivo tumor models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — NK cell-specific KO plus Co-IP complex identification plus mRNA target validation in vivo and in human NK cells\",\n      \"pmids\": [\"38821052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"MCPIP1 overexpression/KD, domain mutant analysis, in vitro RNA cleavage assay, RNA immunoprecipitation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro RNA cleavage assay plus domain mutagenesis plus RIP in single lab\",\n      \"pmids\": [\"25225661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-specific MCPIP1 KO in neutrophils, mRNA stability assays for anti-apoptotic transcripts, apoptosis assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined mRNA target validation, single lab\",\n      \"pmids\": [\"33717148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Macrophage-specific Mcpip1 KO mice, scRNA-seq, RNA-seq, CUT&Tag, luciferase assay, in vivo AP1S2 blockage\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with scRNA-seq pathway dissection and multiple orthogonal methods in single lab\",\n      \"pmids\": [\"37015751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Competitive bone marrow transfer, ILC2-specific Regnase-1 deficiency, mRNA stability assays for Gata3 and Egr1, bleomycin pulmonary fibrosis model\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined mRNA targets with in vivo functional consequences, single lab\",\n      \"pmids\": [\"32978308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"IEC-specific Regnase-1 KO mice, DSS colitis model, metabolomic analysis, mTOR pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype and metabolic analysis, single lab\",\n      \"pmids\": [\"30297433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assay with purified recombinant MCPIP1, 3'-UTR reporter assay for IL-8, siRNA knockdown\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro cleavage with purified protein but single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"27513529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-expression of MCPIP1 and RGS2, C157A mutant analysis, proteasome inhibitor (MG132) treatment\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/overexpression approach, domain mutant supports mechanism, but limited biochemical validation\",\n      \"pmids\": [\"25187114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"RNase-activity-dependent miRNA profiling, mRNA stability assays, MCPIP1 overexpression/RNase-dead mutant in ccRCC cell lines and xenografts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNase-dead mutant plus miRNA and mRNA target validation, single lab\",\n      \"pmids\": [\"34657130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"T cell-conditional Regnase-1/Roquin single and double KO mice, mRNA stability assays, 3'-UTR reporter assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional double KO with defined mRNA targets and cross-regulation, single lab\",\n      \"pmids\": [\"29127149\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZC3H12A/MCPIP1/Regnase-1 is an endoribonuclease that degrades a specific set of inflammatory, immune-regulatory, and metabolic mRNAs by recognizing and cleaving stem-loop structures in their 3'-UTRs in a translation- and UPF1-dependent manner at the ribosome/ER; it also suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops, can deubiquitinate substrates via a separate domain, and is itself post-translationally regulated by IKK- and IRAK1-mediated phosphorylation (leading to proteasomal degradation or 14-3-3-mediated sequestration) and by MALT1-mediated proteolytic cleavage upon TCR activation, collectively making it a central hub for resolving inflammation and maintaining immune homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #11]. 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 [#11]. 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 [#3, #9]. 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 [#0, #8, #12, #23, #25, #27, #29]. Beyond mRNA decay it cleaves pre-miRNA terminal loops to antagonize Dicer and degrades viral RNA, both via the same RNase activity [#4, #6, #26]. 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 [#1, #7, #10, #14]. It also enforces feedback on its own expression by degrading its own mRNA through a 3'-UTR stem-loop [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Macrophage overexpression/KO, mRNA stability and 3'-UTR reporter assays, RNase assay on purified protein\",\n      \"pmids\": [\"19322177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"3'-UTR sequence/structure determinant of substrate selection not yet defined\", \"structural basis of catalysis not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro pre-miRNA cleavage, RNase-domain mutagenesis, miRNA profiling in mammalian cells\",\n      \"pmids\": [\"22055188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"physiological scope of miRNA regulation in vivo unclear\", \"selectivity between pre-miRNA and mRNA substrates undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined how the gene is induced, placing it downstream of IL-1β/MAPK signaling via Elk-1/SRF promoter occupancy.\",\n      \"evidence\": \"Promoter reporter assay, signaling inhibitors, ChIP for Elk-1 and SRF\",\n      \"pmids\": [\"20137095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"additional transcriptional inputs not mapped\", \"link between induction kinetics and inflammatory resolution untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"24270572\", \"23355615\", \"24191027\", \"23706741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether ZC3H12A has intrinsic deubiquitinase catalysis vs. adaptor role unresolved\", \"in vivo significance of antiviral RNA degradation versus mRNA decay not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular fractionation, ribosome profiling, UPF1 knockdown, RNase-dead mutant epistasis in IL-17 signaling\",\n      \"pmids\": [\"26000482\", \"26320658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism coupling translation status to cleavage not yet biochemically reconstituted\", \"how 3'-UTR-independent Il17ra/Il17rc degradation occurs unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro endonuclease and Kd assays, size-exclusion chromatography, active-site mutagenesis (D141N); polysome profiling with NFKBIZ TSE mutants\",\n      \"pmids\": [\"29743536\", \"29471506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"high-resolution structure of enzyme-RNA complex not determined\", \"how decay versus translational silencing is selected on the same transcript unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"28538180\", \"28328949\", \"27513529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"tissue-specific target hierarchy not defined\", \"some target validations rest on single-lab in vitro cleavage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"31329944\", \"31072819\", \"34636324\", \"30842549\", \"31827283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"integration of competing phospho-signals in vivo not quantitatively modeled\", \"cross-talk between localization control and substrate choice incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"34188032\", \"25710910\", \"34811541\", \"31990689\", \"33717148\", \"34657130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"relative contribution of mRNA uridylation versus self-cleavage to Regnase-1 turnover unresolved\", \"structural detail of the Roquin-Regnase-1 complex absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"38821052\", \"37015751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no atomic structure of the catalytically engaged enzyme-RNA-UPF1 complex\", \"quantitative integration of competing regulatory inputs lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 4, 6, 11, 26, 31]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 11, 16, 26]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 18, 32]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 19, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"UPF1\", \"Roquin/RC3H1\", \"MALT1\", \"USP10\", \"NEMO/IKBKG\", \"14-3-3\", \"DDX3X\", \"TUT7/ZCCHC6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}