{"gene":"ZC3H12A","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2012,"finding":"Crystal structure of the MCPIP1 N-terminal conserved domain resolved at 2.0 Å reveals a PIN-like RNase fold; site-specific mutagenesis of acidic residues in the catalytic center abolishes RNase activity, and mutation of positively charged residues on an adjacent arm partially abolishes in vivo RNase activity, identifying the RNA substrate-binding site.","method":"X-ray crystallography + site-directed mutagenesis + in vivo RNase activity assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution structure with functional mutagenesis validation","pmids":["22561375"],"is_preprint":false},{"year":2011,"finding":"IκB kinase (IKK) complex phosphorylates Regnase-1 in response to IL-1R/TLR stimulation, leading to its ubiquitination and proteasomal degradation, thereby releasing inhibition of IL-6 mRNA expression; Regnase-1 also destabilizes its own mRNA via a stem-loop in its 3' UTR, forming a negative feedback loop.","method":"Phosphorylation assay, ubiquitination assay, IL-6 mRNA stability measurement, genetic KO and reconstitution","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods, mechanistic dissection of phosphorylation-degradation axis","pmids":["22037600"],"is_preprint":false},{"year":2013,"finding":"T cell receptor stimulation causes MALT1/paracaspase to cleave Regnase-1 at residue R111, inactivating it and freeing T cells from Regnase-1-mediated suppression of mRNAs including c-Rel, Ox40, and Il2.","method":"In vitro cleavage assay, mutagenesis mapping of cleavage site, T cell functional assays, conditional KO","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical cleavage assay with site identification, validated in primary T cells","pmids":["23706741"],"is_preprint":false},{"year":2014,"finding":"MALT1 paracaspase also cleaves Roquin upon TCR stimulation, and Regnase-1 and Roquin cooperatively repress a shared set of mRNAs (IL-6, ICOS, c-Rel, IRF4, IκBNS, IκBζ) encoding Th17-promoting factors; cooperation requires RNA binding by Roquin and nuclease activity of Regnase-1.","method":"MALT1 cleavage assay, luciferase reporter assay, mutagenesis of nuclease domain, T cell differentiation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical cleavage with domain mutagenesis, replicated across labs","pmids":["25282160"],"is_preprint":false},{"year":2015,"finding":"Regnase-1 and Roquin regulate a common stem-loop structure in inflammatory mRNAs but act at spatiotemporally distinct locations: Regnase-1 cleaves translationally active mRNAs at the ribosome/ER and requires UPF1 helicase activity, whereas Roquin controls translationally inactive mRNAs in P-bodies/stress granules independently of UPF1.","method":"Subcellular fractionation, ribosome profiling, UPF1 knockdown, single-molecule imaging, RNase activity assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including fractionation, imaging, and genetic depletion; replicated","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; it also contains a vertebrate-specific oligomerization domain important for pre-miRNA recognition.","method":"In vitro pre-miRNA cleavage assay, domain mutagenesis, Dicer competition assays, Northern blot","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted cleavage assay with mutagenesis of catalytic domain","pmids":["22055188"],"is_preprint":false},{"year":2013,"finding":"MCPIP1 possesses broad-spectrum antiviral activity by directly binding and degrading viral RNA (JEV, dengue, sindbis, EMCV, influenza, adenovirus) via its RNase and RNA-binding/oligomerization activities but not its deubiquitinase activity.","method":"Viral replication assays, domain-specific mutagenesis, RNA binding and in vitro cleavage assays, MCPIP1 knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro RNA cleavage assay combined with domain mutagenesis and multiple virus models","pmids":["23355615"],"is_preprint":false},{"year":2013,"finding":"MCPIP1 recruits the deubiquitinase USP10 to NEMO via a direct protein-protein interaction, enabling USP10 to remove linear polyubiquitin chains from NEMO, thereby inhibiting IKK activation and NF-κB signaling following genotoxic stress.","method":"Co-immunoprecipitation, deubiquitination assay, siRNA knockdown, NF-κB reporter assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional deubiquitination assay with genetic validation","pmids":["24270572"],"is_preprint":false},{"year":2019,"finding":"IL-17 induces phosphorylation of Regnase-1 via an Act1-TBK1/IKKi-dependent signaling axis, causing phosphorylated Regnase-1 to be released from the ER into the cytosol where it loses mRNA-degrading function, leading to expression of IL-17 target genes; CRISPR-generated mice with blocked IL-17-induced phosphorylation sites are resistant to Th17-mediated inflammation.","method":"Phosphorylation assays, subcellular fractionation, CRISPR/Cas9 knock-in mice, in vivo inflammation models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 — phosphorylation site mapping with CRISPR mutant mice and functional in vivo validation","pmids":["31072819"],"is_preprint":false},{"year":2019,"finding":"UPF1 must first unwind stem-loop structures in target mRNAs before Regnase-1 can cleave them; Regnase-1 physically associates with SMG1-phosphorylated T28 of UPF1 via its RNase domain, and an intrinsically disordered segment of Regnase-1 binds the UPF1 RecA domain to enhance its helicase activity.","method":"Single-molecule imaging, co-immunoprecipitation, in vitro helicase and cleavage assays, SMG1 inhibitor studies, domain mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — single-molecule imaging plus biochemical reconstitution and domain mapping","pmids":["31329944"],"is_preprint":false},{"year":2021,"finding":"Roquin-1 physically interacts with Regnase-1 through a defined interaction surface that includes the sanroque residue; mutations disrupting this interaction impair cooperative post-transcriptional repression of target mRNAs and lead to autoimmunity.","method":"Co-immunoprecipitation, interaction surface mutagenesis, T cell functional assays, mouse autoimmunity models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with mutagenesis of binding interface and in vivo genetic validation","pmids":["34811541"],"is_preprint":false},{"year":2021,"finding":"IL-1β/TLR stimulation dynamically induces formation of a Regnase-1–14-3-3 complex mediated by IRAK1 through a C-terminal domain; phosphorylation of Regnase-1 at S494 and S513 is required for 14-3-3 interaction, which stabilizes Regnase-1 by protecting it from βTRCP-mediated proteasomal degradation but simultaneously inhibits Regnase-1-mRNA association and abolishes mRNA decay; 14-3-3 also abrogates nuclear-cytoplasmic shuttling of Regnase-1.","method":"Regnase-1 interactome by MS, Co-IP, phosphosite mutagenesis, mRNA decay assay, nuclear-cytoplasmic fractionation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — interactome MS with phosphosite mutagenesis and multiple orthogonal functional assays","pmids":["34636324"],"is_preprint":false},{"year":2018,"finding":"MCPIP1 acts as an endonuclease cleaving stem-loop structures at the loop motif and also single-stranded RNA; it binds target RNAs with ~10 nM affinity (Kd); the zinc finger in the PIN domain increases affinity for 25-nt stem-loop RNA; MCPIP1 undergoes homooligomerization during RNA interaction.","method":"In vitro endonuclease assay, equilibrium binding measurements (Kd determination), size-exclusion chromatography, domain deletion analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — quantitative biochemical reconstitution with multiple substrates and domain variants","pmids":["29743536"],"is_preprint":false},{"year":2017,"finding":"Regnase-1 directly degrades mRNAs encoding transferrin receptor 1 (TfR1) and prolyl-hydroxylase-domain protein 3 (PHD3) in vivo, controlling iron homeostasis; loss of Regnase-1 in mice causes iron deficiency anemia via impaired duodenal iron uptake and HIF2α/PHD3 dysregulation; Regnase-1 is itself a HIF2α-inducible gene, providing a positive feedback loop.","method":"Regnase-1 KO mice, mRNA stability assay, RNA-seq, iron metabolism phenotyping, genetic epistasis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with defined molecular targets and epistasis analysis","pmids":["28538180"],"is_preprint":false},{"year":2018,"finding":"In the context of the NFKBIZ translational silencing element (TSE), MCPIP1 suppresses translation (a post-initiation step) in addition to its known endonuclease activity; SL4/5 in the TSE are sufficient for MCPIP1 binding and mRNA destabilization, but SL1-3 are additionally required for translational silencing; MCPIP1 reduces ribosome occupancy and silences even cap-independent (CrPV-IRES) translation.","method":"Luciferase reporter assay, polysome profiling, MCPIP1 knockdown/overexpression, IRES reporter","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal approaches including polysome profiling and IRES reporter with domain analysis","pmids":["29471506"],"is_preprint":false},{"year":2015,"finding":"MCPIP1 endoribonuclease activity (but not deubiquitinase activity) functions as a feedback inhibitor of IL-17 receptor signal transduction and directly degrades Il17ra and Il17rc mRNA independently of the 3' UTR, in addition to degrading Il6 and Nfkbiz mRNAs.","method":"MCPIP1 knockdown/haploinsufficient mice, mRNA stability assay, domain mutagenesis, IL-17 signaling reporter assays, genetic epistasis with Il17ra KO","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 — domain mutagenesis combined with in vivo genetic epistasis and mRNA decay assays","pmids":["26320658"],"is_preprint":false},{"year":2017,"finding":"MCPIP1 directly binds and cleaves C/EBPβ mRNA via endonucleolytic cleavage of stem-loop structures in the 3' UTR, as demonstrated by in vitro cleavage assay, luciferase reporter assay, and RNA immunoprecipitation.","method":"In vitro cleavage assay, luciferase-reporter assay, RNA immunoprecipitation (RIP)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 — reconstituted in vitro cleavage with orthogonal RIP and reporter validation","pmids":["28328949"],"is_preprint":false},{"year":2011,"finding":"MCPIP1 suppresses stress granule (SG) formation and sensitizes cells to apoptosis under stress; SG repression is dependent on MCPIP1 deubiquitinating activity and involves negative regulation of eIF2α phosphorylation.","method":"MCPIP1 overexpression/KO, SG imaging, eIF2α phosphorylation assay, deubiquitinase domain mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — domain mutagenesis with cellular imaging; single lab","pmids":["21971051"],"is_preprint":false},{"year":2013,"finding":"MCPIP1 restricts HIV-1 production in CD4+ T cells by decreasing steady-state viral mRNA levels through its RNase domain; common T-cell stimuli induce rapid proteasomal degradation of MCPIP1, removing this restriction.","method":"Ectopic MCPIP1 expression, MCPIP1 siRNA knockdown, viral mRNA quantification, proteasome inhibitor (MG132) rescue, primary T cell assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — RNase domain requirement shown with domain mutants, validated in primary T cells and T-cell lines","pmids":["24191027"],"is_preprint":false},{"year":2014,"finding":"MCPIP1 directly colocalizies with HCV RNA, can degrade HCV RNA in vitro, and its RNA binding, oligomerization, and RNase activities (but not deubiquitinase) are required to suppress HCV replication.","method":"Immunocytochemistry co-localization, in vitro RNA cleavage assay, domain mutagenesis, knockdown/overexpression, replication-defective HCV mutant","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro RNA cleavage plus domain mutagenesis with orthogonal co-localization","pmids":["25225661"],"is_preprint":false},{"year":2016,"finding":"MCPIP1 degrades IL-8 mRNA through its RNase activity targeting stem-loop/hairpin structures in the IL-8 3' UTR, as shown with purified recombinant MCPIP1 protein in an in vitro cleavage assay.","method":"Recombinant protein purification, in vitro mRNA cleavage assay, 3'UTR reporter analysis","journal":"Journal of innate immunity","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro cleavage with purified recombinant protein","pmids":["27513529"],"is_preprint":false},{"year":2021,"finding":"TUT7 (terminal uridyltransferase 7) directly binds the stem-loop structure in the Zc3h12a (Regnase-1) 3' UTR following TLR4 activation, promoting uridylation and degradation of Regnase-1 mRNA, thereby controlling Regnase-1 protein levels and downstream IL-6 expression.","method":"TUT7 KO mice, RNA immunoprecipitation, 3'-end sequencing (oligo-uridylation detection), TLR4 stimulation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — direct RNA binding demonstrated by RIP, KO mouse with defined molecular mechanism","pmids":["34188032"],"is_preprint":false},{"year":2019,"finding":"Regnase-1 directly targets Tcf7 (encoding TCF-1) mRNA; its deficiency augments TCF-1 expression in CD8+ T cells, promoting formation of TCF-1+ precursor exhausted T cells with enhanced persistence.","method":"Regnase-1 conditional KO, mRNA stability assays, transcriptional/epigenetic profiling, xenograft tumor models","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2–3 — KO with target mRNA identification and functional validation; mRNA decay assay would strengthen","pmids":["33690816"],"is_preprint":false},{"year":2019,"finding":"BATF is identified as a key transcriptional target of Regnase-1 in CD8+ T cells; loss of BATF suppresses the increased accumulation and mitochondrial fitness of Regnase-1-deficient CD8+ T cells, placing BATF downstream of Regnase-1 by genetic epistasis.","method":"In vivo pooled CRISPR-Cas9 screen, secondary genome-scale CRISPR screen, double-KO epistasis, metabolic assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — genome-scale genetic epistasis via double CRISPR KO with functional phenotypic readout","pmids":["31827283"],"is_preprint":false},{"year":2019,"finding":"Regnase-1 regulates HSPC self-renewal by degrading Gata2 and Tal1 mRNAs; loss of Regnase-1 in HSPCs leads to rapid abnormal hematopoiesis.","method":"Conditional KO mice, mRNA stability assay, bone marrow transplantation, RNA-seq","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — KO with mRNA target identification and in vivo phenotype; single lab","pmids":["30842549"],"is_preprint":false},{"year":2016,"finding":"KSHV and EBV precursor miRNAs are directly cleaved by MCPIP1's RNase domain; KSHV infection represses MCPIP1 expression, and KSHV-encoded miRNAs target the MCPIP1 3' UTR to suppress its expression, representing a viral immune evasion mechanism.","method":"In vitro pre-miRNA cleavage assay, siRNA knockdown, luciferase 3'UTR reporter, de novo KSHV infection model","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro cleavage plus 3'UTR reporter with viral infection model","pmids":["27893764"],"is_preprint":false},{"year":2015,"finding":"IL-17 stabilizes Zc3h12a mRNA via a CIKS–DDX3X complex; IL-17 stimulation promotes CIKS–DDX3X interaction (requiring the DDX3X helicase domain), DDX3X directly binds Zc3h12a mRNA, and IKKε, TRAF2, and TRAF5 are also required for this stabilization.","method":"Co-immunoprecipitation, DDX3X knockdown, mRNA half-life assay, RNA immunoprecipitation","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus RNA-IP and mRNA decay assay; single lab","pmids":["25710910"],"is_preprint":false},{"year":2021,"finding":"Regnase-1 suppresses mRNAs encoding Gata3 and Egr1 in ILC2s to control their profibrotic function; Regnase-1-deficient ILC2s spontaneously proliferate and activate and augment bleomycin-induced pulmonary fibrosis.","method":"Competitive bone marrow transfer, RNA-seq of Regnase-1-deficient ILC2s, bleomycin fibrosis model, mRNA target validation","journal":"The European respiratory journal","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined mRNA targets and in vivo disease model; single lab","pmids":["32978308"],"is_preprint":false},{"year":2020,"finding":"IKK complex-mediated phosphorylation of Regnase-1 at S435/S439 is essential for IL-33- and IL-25-induced ILC2 activation; Regnase-1 S435A/S439A knock-in mice retain Regnase-1 protein and show reduced ILC2 proliferation, cytokine production, and type 2 pulmonary inflammation in vivo.","method":"Phospho-mutant knock-in mice (S435A/S439A), ILC2 stimulation assays, in vivo cytokine challenge models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 — phospho-mutant knock-in mice with defined phosphorylation sites and in vivo functional validation","pmids":["31990689"],"is_preprint":false},{"year":2017,"finding":"MCPIP1 regulates C/EBPβ and C/EBPδ mRNA levels as direct targets of its RNase activity in macrophages, and pharmacological inhibition of MALT1 (which cleaves MCPIP1) increases MCPIP1 protein and protects mice from LPS-induced lung injury.","method":"Myeloid-specific KO mice, mRNA stability assay, MI-2 MALT1 inhibitor treatment, in vivo LPS model","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with mRNA target identification and pharmacologic validation in vivo","pmids":["29263935"],"is_preprint":false},{"year":2018,"finding":"Regnase-1 controls colon epithelial regeneration by regulating mTORC1 signaling and purine metabolism; intestinal epithelial-specific deletion of Regnase-1 increases cell proliferation, decreases apoptosis, and attenuates DSS-induced colitis and tumor progression.","method":"Intestinal epithelial-specific KO mice, metabolomics, mTOR pathway analysis, DSS colitis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KO with pathway identification; mechanistic link to specific Regnase-1 targets not fully established","pmids":["30297433"],"is_preprint":false},{"year":2024,"finding":"Regnase-1 deletion in NK cells increases anti-tumor IFN-γ production via elevated OCT2 and IκBζ mRNA targets; OCT2 and IκBζ form a complex with NF-κB to induce Ifng transcription, and IFN-γ induces CXCL16 on myeloid cells to recruit CXCR6+ NK cells.","method":"NK cell-specific Regnase-1 KO, mRNA target identification, co-IP of OCT2-IκBζ-NF-κB complex, in vivo tumor models","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — NK cell-specific KO with defined transcriptional complex and in vivo functional validation","pmids":["38821052"],"is_preprint":false},{"year":2010,"finding":"IL-1β induces ZC3H12A/MCPIP1 expression through the MAP kinase pathway and transcription factors Elk-1 and SRF, which bind a ZC3H12A promoter region from -76 to +60; chromatin immunoprecipitation confirmed in vivo binding of both Elk-1 and SRF to this promoter region.","method":"Reporter assay with promoter deletion constructs, ChIP, MAP kinase pathway inhibitors, primary macrophages","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus reporter assays with functional inhibitor studies; single lab","pmids":["20137095"],"is_preprint":false},{"year":2022,"finding":"Antisense morpholino oligonucleotides targeting the stem-loop structures in Regnase-1's own 3'UTR block Regnase-1 self-regulation, stabilizing Regnase-1 mRNA and increasing Regnase-1 protein, which then degrades multiple proinflammatory target mRNAs; intratracheal or intracranial delivery ameliorates inflammatory disease in vivo.","method":"Antisense oligonucleotide treatment, mRNA stability assay, macrophage cytokine profiling, in vivo ARDS and EAE models","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of self-regulatory stem-loop with therapeutic in vivo validation","pmids":["35544597"],"is_preprint":false},{"year":2022,"finding":"Macrophage-specific Mcpip1 deficiency arrests monocyte-to-macrophage maturation via an ATF3–AP1S2 signaling axis; silencing Ap1s2 or Atf3 suppressed MCPIP1-deficient macrophage M1-like polarization and cytokine production, and in vivo blockage of Ap1s2 ameliorated DSS colitis.","method":"scRNA-seq, macrophage-specific KO, RNA-seq, CUT&Tag, luciferase assay, in vivo colitis model with Ap1s2 blockage","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal omics and genetic approaches with in vivo rescue","pmids":["37015751"],"is_preprint":false}],"current_model":"ZC3H12A/Regnase-1/MCPIP1 is an endoribonuclease with a PIN-like catalytic domain that recognizes stem-loop structures in the 3' UTRs of target mRNAs (including IL-6, IL-12, IL-2, c-Rel, TfR1, and many others) and cleaves them co-translationally at the ribosome/ER in a UPF1 helicase-dependent manner; its activity is dynamically regulated by IKK-mediated phosphorylation and proteasomal degradation, MALT1-mediated proteolytic cleavage at R111 upon TCR stimulation, IRAK1-mediated 14-3-3 interaction that sequesters it from mRNA, IL-17-induced Act1-TBK1/IKKi phosphorylation that releases it from the ER, and TUT7-mediated uridylation of its own mRNA; it additionally suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops to antagonize Dicer, cooperates physically with Roquin-1 through a defined interaction surface for synergistic mRNA repression, and recruits USP10 to deubiquitinate NEMO to terminate NF-κB signaling, collectively placing Regnase-1 as a master post-transcriptional brake on inflammation across innate and adaptive immune cells."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing transcriptional control: identification of how ZC3H12A expression is itself induced revealed that it is an immediate-early gene driven by IL-1β through MAP kinase–Elk-1/SRF signaling at a compact promoter region.","evidence":"Promoter deletion reporters, ChIP for Elk-1/SRF, MAP kinase inhibitors in primary macrophages","pmids":["20137095"],"confidence":"Medium","gaps":["Single lab; no genome-wide identification of additional transcription factors","Upstream chromatin context not addressed","Regulation by signals other than IL-1β at this promoter not tested"]},{"year":2011,"claim":"Defining the enzymatic mechanism and its regulation: three concurrent studies established that Regnase-1 is a bona fide endoribonuclease that degrades IL-6 mRNA, is regulated by IKK-mediated phosphorylation and proteasomal degradation forming a negative feedback loop, and additionally suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops.","evidence":"Phosphorylation/ubiquitination assays with genetic KO (IL-6 axis); in vitro pre-miRNA cleavage with domain mutagenesis and Dicer competition (miRNA axis); mRNA half-life measurements","pmids":["22037600","22055188"],"confidence":"High","gaps":["Structural basis of RNA recognition not yet resolved","Identity of the full target mRNA repertoire unknown","Relative contribution of mRNA decay vs. miRNA suppression in vivo unresolved"]},{"year":2012,"claim":"Solving the atomic structure of the catalytic domain revealed a PIN-like RNase fold and identified both the catalytic acidic residues and a positively charged RNA-binding arm, providing the structural framework for understanding substrate recognition.","evidence":"2.0 Å X-ray crystal structure with site-directed mutagenesis abolishing RNase activity","pmids":["22561375"],"confidence":"High","gaps":["No RNA-bound co-crystal structure","Zinc finger and oligomerization domain structures not resolved","Structural basis for stem-loop selectivity unknown"]},{"year":2013,"claim":"Discovery of MALT1-mediated cleavage at R111 upon TCR stimulation established how adaptive immune activation inactivates Regnase-1, freeing T cells from its suppressive activity on c-Rel, Ox40, and Il2 mRNAs.","evidence":"In vitro MALT1 cleavage assay with site mapping, validated in conditional KO T cells","pmids":["23706741"],"confidence":"High","gaps":["Kinetics of MALT1 cleavage relative to other regulatory inputs not defined","Whether MALT1 cleavage products have residual function unknown"]},{"year":2013,"claim":"Demonstration that Regnase-1 has broad-spectrum antiviral activity through direct RNase-mediated degradation of viral RNA expanded its role beyond endogenous mRNA regulation to innate antiviral defense.","evidence":"In vitro viral RNA cleavage, domain mutagenesis across multiple virus models (JEV, DENV, HIV, HCV, influenza)","pmids":["23355615","24191027","25225661"],"confidence":"High","gaps":["In vivo antiviral efficacy not demonstrated for all viruses","Mechanism of viral RNA recognition specificity vs. host mRNA unclear","Viral countermeasures beyond KSHV not characterized"]},{"year":2013,"claim":"Identification of USP10 recruitment to NEMO for linear polyubiquitin removal revealed a non-catalytic scaffolding function of Regnase-1 in terminating NF-κB signaling, distinct from its RNase activity.","evidence":"Reciprocal co-immunoprecipitation, deubiquitination assay, siRNA knockdown, NF-κB reporter","pmids":["24270572"],"confidence":"High","gaps":["Whether USP10 recruitment requires specific Regnase-1 domains beyond those tested","Relevance across cell types beyond genotoxic stress context","Relationship to RNase-dependent NF-κB regulation unclear"]},{"year":2015,"claim":"Spatiotemporal dissection established that Regnase-1 and Roquin regulate the same mRNAs but in distinct compartments — Regnase-1 cleaves translationally active mRNAs at the ER/ribosome via UPF1 helicase, while Roquin acts in P-bodies/stress granules — resolving how two seemingly redundant pathways cooperate.","evidence":"Subcellular fractionation, single-molecule imaging, UPF1 knockdown, polysome association","pmids":["26000482"],"confidence":"High","gaps":["How Regnase-1 is recruited to specific translating mRNAs vs. bulk translation unknown","Stoichiometry of UPF1–Regnase-1 complex at the ribosome unresolved","Whether other helicases substitute for UPF1 untested"]},{"year":2015,"claim":"Expansion of the target repertoire to IL-17 receptor subunits (Il17ra, Il17rc) and identification of 3′ UTR-independent degradation demonstrated that Regnase-1 acts as a feedback inhibitor of IL-17 signaling at multiple levels.","evidence":"MCPIP1 haploinsufficient mice, mRNA stability assay, domain mutagenesis, genetic epistasis with Il17ra KO","pmids":["26320658"],"confidence":"High","gaps":["Mechanism of 3′ UTR-independent target recognition not defined","Whether coding-region stem-loops serve as recognition elements unknown"]},{"year":2017,"claim":"Identification of TfR1 and PHD3 as direct Regnase-1 targets linked its endoribonuclease activity to iron homeostasis and HIF signaling, demonstrating functions far beyond cytokine mRNA decay.","evidence":"Regnase-1 KO mice with iron metabolism phenotyping, mRNA stability assay, genetic epistasis","pmids":["28538180"],"confidence":"High","gaps":["Whether iron dysregulation contributes to immunological phenotypes of KO mice unclear","Full scope of metabolic targets unknown"]},{"year":2018,"claim":"Biochemical reconstitution quantified Regnase-1's RNA binding affinity (~10 nM Kd for stem-loop substrates) and demonstrated that it oligomerizes during RNA interaction, with the zinc finger enhancing stem-loop recognition; separately, Regnase-1 was shown to suppress translation post-initiation in addition to cleaving mRNA.","evidence":"Equilibrium binding measurements, SEC for oligomerization, polysome profiling with CrPV-IRES reporter","pmids":["29471506","29743536"],"confidence":"High","gaps":["Structural basis of oligomerization unknown","Whether translational suppression is separable from cleavage in vivo unresolved","Contribution of translational silencing vs. decay to target regulation not quantified"]},{"year":2019,"claim":"The molecular basis of UPF1 cooperation was resolved: Regnase-1 binds SMG1-phosphorylated UPF1 via its RNase domain while an intrinsically disordered segment enhances UPF1 helicase activity, and IL-17 signaling was shown to phosphorylate Regnase-1 via Act1–TBK1/IKKi, releasing it from the ER and abolishing its function.","evidence":"Single-molecule imaging, in vitro helicase/cleavage assays, CRISPR phospho-mutant knock-in mice with in vivo inflammation models","pmids":["31329944","31072819"],"confidence":"High","gaps":["Whether ER-to-cytosol translocation involves other chaperones/cofactors","Structural model of UPF1–Regnase-1 complex lacking","How IL-17-induced phosphorylation is reversed to restore Regnase-1 function unknown"]},{"year":2019,"claim":"Genome-scale CRISPR screening in CD8+ T cells identified BATF as a key downstream mediator of Regnase-1's control of T cell fitness, establishing Regnase-1 as a checkpoint for anti-tumor T cell function.","evidence":"In vivo pooled CRISPR screen, double-KO epistasis, metabolic assays in CD8+ T cells","pmids":["31827283"],"confidence":"High","gaps":["Whether BATF mRNA is a direct cleavage substrate or indirect target not fully resolved","Relative importance of multiple Regnase-1 targets in CD8+ T cell context unknown"]},{"year":2021,"claim":"Three regulatory layers were simultaneously clarified: the Roquin-1–Regnase-1 physical interaction surface was mapped (mutations cause autoimmunity), IRAK1-dependent phosphorylation at S494/S513 creates a 14-3-3 binding site that sequesters Regnase-1 from mRNA while protecting it from degradation, and TUT7-mediated uridylation of Regnase-1's own mRNA provides an additional layer of post-transcriptional control of Regnase-1 protein levels.","evidence":"Interaction surface mutagenesis and mouse autoimmunity models; interactome MS with phosphosite mutagenesis and nuclear-cytoplasmic fractionation; TUT7 KO mice with 3′-end sequencing","pmids":["34811541","34636324","34188032"],"confidence":"High","gaps":["Whether 14-3-3 sequestration and ER localization are coordinated or independent regulatory modes","Kinetic modeling integrating all regulatory inputs lacking","Whether TUT7 regulation extends to other cell types beyond macrophages"]},{"year":2022,"claim":"Therapeutic exploitation of Regnase-1's self-regulatory stem-loop was demonstrated: antisense oligonucleotides blocking the 3′ UTR stem-loop stabilize Regnase-1 mRNA, boost its protein, and suppress inflammation in ARDS and EAE models, providing proof-of-concept for pharmacological enhancement of endogenous Regnase-1.","evidence":"Antisense morpholino treatment, mRNA stability assay, intratracheal/intracranial delivery in vivo","pmids":["35544597"],"confidence":"High","gaps":["Long-term safety and off-target effects of ASO not assessed","Whether chronic Regnase-1 elevation impairs adaptive immunity unknown","Pharmacokinetics and tissue specificity of delivery not optimized"]},{"year":2024,"claim":"Extension to NK cell biology revealed that Regnase-1 controls anti-tumor IFN-γ production through degradation of OCT2 and IκBζ mRNAs, which form a complex with NF-κB to drive Ifng transcription and CXCL16-mediated NK recruitment.","evidence":"NK cell-specific KO, mRNA target identification, co-IP of OCT2–IκBζ–NF-κB complex, tumor models","pmids":["38821052"],"confidence":"High","gaps":["Whether OCT2 mRNA is directly cleaved by Regnase-1 via canonical stem-loop mechanism not shown biochemically","Interplay between NK cell and T cell Regnase-1 regulation in tumors unclear"]},{"year":null,"claim":"Key unresolved questions include the structural basis for stem-loop selectivity (no RNA-bound co-crystal structure exists), the comprehensive target repertoire across cell types, how multiple phosphorylation-based regulatory inputs are temporally integrated, and whether Regnase-1's translational suppression function is mechanistically separable from its endonuclease activity in vivo.","evidence":"","pmids":[],"confidence":"High","gaps":["No RNA-bound co-crystal or cryo-EM structure","No single-cell-resolved target atlas across immune and non-immune lineages","Quantitative kinetic model integrating IKK, MALT1, 14-3-3, TBK1, and TUT7 inputs absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,5,6,12,16,20,25]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,12,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,14]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,8,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,3,15,28,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,8,11]}],"complexes":["Regnase-1–UPF1 complex","Regnase-1–Roquin-1 complex","Regnase-1–14-3-3 complex"],"partners":["UPF1","RC3H1","MALT1","USP10","YWHAB","TUT7","IRAK1","DDX3X"],"other_free_text":[]},"mechanistic_narrative":"ZC3H12A (Regnase-1/MCPIP1) is a PIN domain endoribonuclease that functions as a master post-transcriptional brake on inflammation by recognizing and cleaving stem-loop structures in the 3′ UTRs of proinflammatory mRNAs — including IL-6, IL-12, c-Rel, NFKBIZ, IL-8, C/EBPβ, and IL-17 receptor subunits — as well as viral RNAs and precursor miRNAs [PMID:22561375, PMID:26000482, PMID:22055188, PMID:23355615, PMID:27513529]. Regnase-1 acts co-translationally at the ribosome/ER in a UPF1 helicase-dependent manner, where UPF1 unwinds target stem-loops to enable cleavage, and it physically cooperates with the RNA-binding protein Roquin-1 through a defined interaction surface to synergistically repress shared inflammatory transcripts [PMID:26000482, PMID:31329944, PMID:34811541]. Its activity is dynamically controlled by IKK-mediated phosphorylation leading to proteasomal degradation upon TLR/IL-1R signaling, MALT1 paracaspase cleavage at R111 upon TCR stimulation, IRAK1-dependent 14-3-3 sequestration that blocks mRNA access, Act1–TBK1/IKKi phosphorylation that releases it from the ER upon IL-17 stimulation, and TUT7-mediated uridylation of its own mRNA, while Regnase-1 also auto-regulates by destabilizing its own transcript via a 3′ UTR stem-loop [PMID:22037600, PMID:23706741, PMID:34636324, PMID:31072819, PMID:34188032]. Beyond mRNA decay, Regnase-1 suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops in competition with Dicer, recruits the deubiquitinase USP10 to NEMO to terminate NF-κB signaling, and regulates diverse cell fates in T cells, NK cells, ILC2s, HSPCs, and intestinal epithelium through degradation of lineage-specific transcripts such as BATF, Tcf7, Gata2, and Gata3 [PMID:22055188, PMID:24270572, PMID:31827283, PMID:30842549, PMID:32978308]."},"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":"31827283","id":"PMC_31827283","title":"Targeting 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site-specific mutagenesis of acidic residues in the catalytic center abolishes RNase activity, and mutation of positively charged residues on an adjacent arm partially abolishes in vivo RNase activity, identifying the RNA substrate-binding site.\",\n      \"method\": \"X-ray crystallography + site-directed mutagenesis + in vivo RNase activity assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution structure with functional mutagenesis validation\",\n      \"pmids\": [\"22561375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IκB kinase (IKK) complex phosphorylates Regnase-1 in response to IL-1R/TLR stimulation, leading to its ubiquitination and proteasomal degradation, thereby releasing inhibition of IL-6 mRNA expression; Regnase-1 also destabilizes its own mRNA via a stem-loop in its 3' UTR, forming a negative feedback loop.\",\n      \"method\": \"Phosphorylation assay, ubiquitination assay, IL-6 mRNA stability measurement, genetic KO and reconstitution\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods, mechanistic dissection of phosphorylation-degradation axis\",\n      \"pmids\": [\"22037600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"T cell receptor stimulation causes MALT1/paracaspase to cleave Regnase-1 at residue R111, inactivating it and freeing T cells from Regnase-1-mediated suppression of mRNAs including c-Rel, Ox40, and Il2.\",\n      \"method\": \"In vitro cleavage assay, mutagenesis mapping of cleavage site, T cell functional assays, conditional KO\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical cleavage assay with site identification, validated in primary T cells\",\n      \"pmids\": [\"23706741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MALT1 paracaspase also cleaves Roquin upon TCR stimulation, and Regnase-1 and Roquin cooperatively repress a shared set of mRNAs (IL-6, ICOS, c-Rel, IRF4, IκBNS, IκBζ) encoding Th17-promoting factors; cooperation requires RNA binding by Roquin and nuclease activity of Regnase-1.\",\n      \"method\": \"MALT1 cleavage assay, luciferase reporter assay, mutagenesis of nuclease domain, T cell differentiation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical cleavage with domain mutagenesis, replicated across labs\",\n      \"pmids\": [\"25282160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Regnase-1 and Roquin regulate a common stem-loop structure in inflammatory mRNAs but act at spatiotemporally distinct locations: Regnase-1 cleaves translationally active mRNAs at the ribosome/ER and requires UPF1 helicase activity, whereas Roquin controls translationally inactive mRNAs in P-bodies/stress granules independently of UPF1.\",\n      \"method\": \"Subcellular fractionation, ribosome profiling, UPF1 knockdown, single-molecule imaging, RNase activity assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including fractionation, imaging, and genetic depletion; replicated\",\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; it also contains a vertebrate-specific oligomerization domain important for pre-miRNA recognition.\",\n      \"method\": \"In vitro pre-miRNA cleavage assay, domain mutagenesis, Dicer competition assays, Northern blot\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted cleavage assay with mutagenesis of catalytic domain\",\n      \"pmids\": [\"22055188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MCPIP1 possesses broad-spectrum antiviral activity by directly binding and degrading viral RNA (JEV, dengue, sindbis, EMCV, influenza, adenovirus) via its RNase and RNA-binding/oligomerization activities but not its deubiquitinase activity.\",\n      \"method\": \"Viral replication assays, domain-specific mutagenesis, RNA binding and in vitro cleavage assays, MCPIP1 knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro RNA cleavage assay combined with domain mutagenesis and multiple virus models\",\n      \"pmids\": [\"23355615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MCPIP1 recruits the deubiquitinase USP10 to NEMO via a direct protein-protein interaction, enabling USP10 to remove linear polyubiquitin chains from NEMO, thereby inhibiting IKK activation and NF-κB signaling following genotoxic stress.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, siRNA knockdown, NF-κB reporter assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional deubiquitination assay with genetic validation\",\n      \"pmids\": [\"24270572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17 induces phosphorylation of Regnase-1 via an Act1-TBK1/IKKi-dependent signaling axis, causing phosphorylated Regnase-1 to be released from the ER into the cytosol where it loses mRNA-degrading function, leading to expression of IL-17 target genes; CRISPR-generated mice with blocked IL-17-induced phosphorylation sites are resistant to Th17-mediated inflammation.\",\n      \"method\": \"Phosphorylation assays, subcellular fractionation, CRISPR/Cas9 knock-in mice, in vivo inflammation models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — phosphorylation site mapping with CRISPR mutant mice and functional in vivo validation\",\n      \"pmids\": [\"31072819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UPF1 must first unwind stem-loop structures in target mRNAs before Regnase-1 can cleave them; Regnase-1 physically associates with SMG1-phosphorylated T28 of UPF1 via its RNase domain, and an intrinsically disordered segment of Regnase-1 binds the UPF1 RecA domain to enhance its helicase activity.\",\n      \"method\": \"Single-molecule imaging, co-immunoprecipitation, in vitro helicase and cleavage assays, SMG1 inhibitor studies, domain mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — single-molecule imaging plus biochemical reconstitution and domain mapping\",\n      \"pmids\": [\"31329944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Roquin-1 physically interacts with Regnase-1 through a defined interaction surface that includes the sanroque residue; mutations disrupting this interaction impair cooperative post-transcriptional repression of target mRNAs and lead to autoimmunity.\",\n      \"method\": \"Co-immunoprecipitation, interaction surface mutagenesis, T cell functional assays, mouse autoimmunity models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mutagenesis of binding interface and in vivo genetic validation\",\n      \"pmids\": [\"34811541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-1β/TLR stimulation dynamically induces formation of a Regnase-1–14-3-3 complex mediated by IRAK1 through a C-terminal domain; phosphorylation of Regnase-1 at S494 and S513 is required for 14-3-3 interaction, which stabilizes Regnase-1 by protecting it from βTRCP-mediated proteasomal degradation but simultaneously inhibits Regnase-1-mRNA association and abolishes mRNA decay; 14-3-3 also abrogates nuclear-cytoplasmic shuttling of Regnase-1.\",\n      \"method\": \"Regnase-1 interactome by MS, Co-IP, phosphosite mutagenesis, mRNA decay assay, nuclear-cytoplasmic fractionation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — interactome MS with phosphosite mutagenesis and multiple orthogonal functional 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 single-stranded RNA; it binds target RNAs with ~10 nM affinity (Kd); the zinc finger in the PIN domain increases affinity for 25-nt stem-loop RNA; MCPIP1 undergoes homooligomerization during RNA interaction.\",\n      \"method\": \"In vitro endonuclease assay, equilibrium binding measurements (Kd determination), size-exclusion chromatography, domain deletion analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative biochemical reconstitution with multiple substrates and domain variants\",\n      \"pmids\": [\"29743536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Regnase-1 directly degrades mRNAs encoding transferrin receptor 1 (TfR1) and prolyl-hydroxylase-domain protein 3 (PHD3) in vivo, controlling iron homeostasis; loss of Regnase-1 in mice causes iron deficiency anemia via impaired duodenal iron uptake and HIF2α/PHD3 dysregulation; Regnase-1 is itself a HIF2α-inducible gene, providing a positive feedback loop.\",\n      \"method\": \"Regnase-1 KO mice, mRNA stability assay, RNA-seq, iron metabolism phenotyping, genetic epistasis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined molecular targets and epistasis analysis\",\n      \"pmids\": [\"28538180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In the context of the NFKBIZ translational silencing element (TSE), MCPIP1 suppresses translation (a post-initiation step) in addition to its known endonuclease activity; SL4/5 in the TSE are sufficient for MCPIP1 binding and mRNA destabilization, but SL1-3 are additionally required for translational silencing; MCPIP1 reduces ribosome occupancy and silences even cap-independent (CrPV-IRES) translation.\",\n      \"method\": \"Luciferase reporter assay, polysome profiling, MCPIP1 knockdown/overexpression, IRES reporter\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal approaches including polysome profiling and IRES reporter with domain analysis\",\n      \"pmids\": [\"29471506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MCPIP1 endoribonuclease activity (but not deubiquitinase activity) functions as a feedback inhibitor of IL-17 receptor signal transduction and directly degrades Il17ra and Il17rc mRNA independently of the 3' UTR, in addition to degrading Il6 and Nfkbiz mRNAs.\",\n      \"method\": \"MCPIP1 knockdown/haploinsufficient mice, mRNA stability assay, domain mutagenesis, IL-17 signaling reporter assays, genetic epistasis with Il17ra KO\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain mutagenesis combined with in vivo genetic epistasis and mRNA decay assays\",\n      \"pmids\": [\"26320658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MCPIP1 directly binds and cleaves C/EBPβ mRNA via endonucleolytic cleavage of stem-loop structures in the 3' UTR, as demonstrated by in vitro cleavage assay, luciferase reporter assay, and RNA immunoprecipitation.\",\n      \"method\": \"In vitro cleavage assay, luciferase-reporter assay, RNA immunoprecipitation (RIP)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstituted in vitro cleavage with orthogonal RIP and reporter validation\",\n      \"pmids\": [\"28328949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MCPIP1 suppresses stress granule (SG) formation and sensitizes cells to apoptosis under stress; SG repression is dependent on MCPIP1 deubiquitinating activity and involves negative regulation of eIF2α phosphorylation.\",\n      \"method\": \"MCPIP1 overexpression/KO, SG imaging, eIF2α phosphorylation assay, deubiquitinase domain mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — domain mutagenesis with cellular imaging; single lab\",\n      \"pmids\": [\"21971051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MCPIP1 restricts HIV-1 production in CD4+ T cells by decreasing steady-state viral mRNA levels through its RNase domain; common T-cell stimuli induce rapid proteasomal degradation of MCPIP1, removing this restriction.\",\n      \"method\": \"Ectopic MCPIP1 expression, MCPIP1 siRNA knockdown, viral mRNA quantification, proteasome inhibitor (MG132) rescue, primary T cell assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNase domain requirement shown with domain mutants, validated in primary T cells and T-cell lines\",\n      \"pmids\": [\"24191027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MCPIP1 directly colocalizies with HCV RNA, can degrade HCV RNA in vitro, and its RNA binding, oligomerization, and RNase activities (but not deubiquitinase) are required to suppress HCV replication.\",\n      \"method\": \"Immunocytochemistry co-localization, in vitro RNA cleavage assay, domain mutagenesis, knockdown/overexpression, replication-defective HCV mutant\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro RNA cleavage plus domain mutagenesis with orthogonal co-localization\",\n      \"pmids\": [\"25225661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MCPIP1 degrades IL-8 mRNA through its RNase activity targeting stem-loop/hairpin structures in the IL-8 3' UTR, as shown with purified recombinant MCPIP1 protein in an in vitro cleavage assay.\",\n      \"method\": \"Recombinant protein purification, in vitro mRNA cleavage assay, 3'UTR reporter analysis\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro cleavage with purified recombinant protein\",\n      \"pmids\": [\"27513529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TUT7 (terminal uridyltransferase 7) directly binds the stem-loop structure in the Zc3h12a (Regnase-1) 3' UTR following TLR4 activation, promoting uridylation and degradation of Regnase-1 mRNA, thereby controlling Regnase-1 protein levels and downstream IL-6 expression.\",\n      \"method\": \"TUT7 KO mice, RNA immunoprecipitation, 3'-end sequencing (oligo-uridylation detection), TLR4 stimulation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA binding demonstrated by RIP, KO mouse with defined molecular mechanism\",\n      \"pmids\": [\"34188032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Regnase-1 directly targets Tcf7 (encoding TCF-1) mRNA; its deficiency augments TCF-1 expression in CD8+ T cells, promoting formation of TCF-1+ precursor exhausted T cells with enhanced persistence.\",\n      \"method\": \"Regnase-1 conditional KO, mRNA stability assays, transcriptional/epigenetic profiling, xenograft tumor models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — KO with target mRNA identification and functional validation; mRNA decay assay would strengthen\",\n      \"pmids\": [\"33690816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BATF is identified as a key transcriptional target of Regnase-1 in CD8+ T cells; loss of BATF suppresses the increased accumulation and mitochondrial fitness of Regnase-1-deficient CD8+ T cells, placing BATF downstream of Regnase-1 by genetic epistasis.\",\n      \"method\": \"In vivo pooled CRISPR-Cas9 screen, secondary genome-scale CRISPR screen, double-KO epistasis, metabolic assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-scale genetic epistasis via double CRISPR KO with functional phenotypic readout\",\n      \"pmids\": [\"31827283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Regnase-1 regulates HSPC self-renewal by degrading Gata2 and Tal1 mRNAs; loss of Regnase-1 in HSPCs leads to rapid abnormal hematopoiesis.\",\n      \"method\": \"Conditional KO mice, mRNA stability assay, bone marrow transplantation, RNA-seq\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with mRNA target identification and in vivo phenotype; single lab\",\n      \"pmids\": [\"30842549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KSHV and EBV precursor miRNAs are directly cleaved by MCPIP1's RNase domain; KSHV infection represses MCPIP1 expression, and KSHV-encoded miRNAs target the MCPIP1 3' UTR to suppress its expression, representing a viral immune evasion mechanism.\",\n      \"method\": \"In vitro pre-miRNA cleavage assay, siRNA knockdown, luciferase 3'UTR reporter, de novo KSHV infection model\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro cleavage plus 3'UTR reporter with viral infection model\",\n      \"pmids\": [\"27893764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17 stabilizes Zc3h12a mRNA via a CIKS–DDX3X complex; IL-17 stimulation promotes CIKS–DDX3X interaction (requiring the DDX3X helicase domain), DDX3X directly binds Zc3h12a mRNA, and IKKε, TRAF2, and TRAF5 are also required for this stabilization.\",\n      \"method\": \"Co-immunoprecipitation, DDX3X knockdown, mRNA half-life assay, RNA immunoprecipitation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus RNA-IP and mRNA decay assay; single lab\",\n      \"pmids\": [\"25710910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Regnase-1 suppresses mRNAs encoding Gata3 and Egr1 in ILC2s to control their profibrotic function; Regnase-1-deficient ILC2s spontaneously proliferate and activate and augment bleomycin-induced pulmonary fibrosis.\",\n      \"method\": \"Competitive bone marrow transfer, RNA-seq of Regnase-1-deficient ILC2s, bleomycin fibrosis model, mRNA target validation\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined mRNA targets and in vivo disease model; single lab\",\n      \"pmids\": [\"32978308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IKK complex-mediated phosphorylation of Regnase-1 at S435/S439 is essential for IL-33- and IL-25-induced ILC2 activation; Regnase-1 S435A/S439A knock-in mice retain Regnase-1 protein and show reduced ILC2 proliferation, cytokine production, and type 2 pulmonary inflammation in vivo.\",\n      \"method\": \"Phospho-mutant knock-in mice (S435A/S439A), ILC2 stimulation assays, in vivo cytokine challenge models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — phospho-mutant knock-in mice with defined phosphorylation sites and in vivo functional validation\",\n      \"pmids\": [\"31990689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MCPIP1 regulates C/EBPβ and C/EBPδ mRNA levels as direct targets of its RNase activity in macrophages, and pharmacological inhibition of MALT1 (which cleaves MCPIP1) increases MCPIP1 protein and protects mice from LPS-induced lung injury.\",\n      \"method\": \"Myeloid-specific KO mice, mRNA stability assay, MI-2 MALT1 inhibitor treatment, in vivo LPS model\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with mRNA target identification and pharmacologic validation in vivo\",\n      \"pmids\": [\"29263935\"],\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-specific deletion of Regnase-1 increases cell proliferation, decreases apoptosis, and attenuates DSS-induced colitis and tumor progression.\",\n      \"method\": \"Intestinal epithelial-specific KO mice, metabolomics, mTOR pathway analysis, DSS colitis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with pathway identification; mechanistic link to specific Regnase-1 targets not fully established\",\n      \"pmids\": [\"30297433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Regnase-1 deletion in NK cells increases anti-tumor IFN-γ production via elevated OCT2 and IκBζ mRNA targets; OCT2 and IκBζ form a complex with NF-κB to induce Ifng transcription, and IFN-γ induces CXCL16 on myeloid cells to recruit CXCR6+ NK cells.\",\n      \"method\": \"NK cell-specific Regnase-1 KO, mRNA target identification, co-IP of OCT2-IκBζ-NF-κB complex, in vivo tumor models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — NK cell-specific KO with defined transcriptional complex and in vivo functional validation\",\n      \"pmids\": [\"38821052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-1β induces ZC3H12A/MCPIP1 expression through the MAP kinase pathway and transcription factors Elk-1 and SRF, which bind a ZC3H12A promoter region from -76 to +60; chromatin immunoprecipitation confirmed in vivo binding of both Elk-1 and SRF to this promoter region.\",\n      \"method\": \"Reporter assay with promoter deletion constructs, ChIP, MAP kinase pathway inhibitors, primary macrophages\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assays with functional inhibitor studies; single lab\",\n      \"pmids\": [\"20137095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Antisense morpholino oligonucleotides targeting the stem-loop structures in Regnase-1's own 3'UTR block Regnase-1 self-regulation, stabilizing Regnase-1 mRNA and increasing Regnase-1 protein, which then degrades multiple proinflammatory target mRNAs; intratracheal or intracranial delivery ameliorates inflammatory disease in vivo.\",\n      \"method\": \"Antisense oligonucleotide treatment, mRNA stability assay, macrophage cytokine profiling, in vivo ARDS and EAE models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of self-regulatory stem-loop with therapeutic in vivo validation\",\n      \"pmids\": [\"35544597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Macrophage-specific Mcpip1 deficiency arrests monocyte-to-macrophage maturation via an ATF3–AP1S2 signaling axis; silencing Ap1s2 or Atf3 suppressed MCPIP1-deficient macrophage M1-like polarization and cytokine production, and in vivo blockage of Ap1s2 ameliorated DSS colitis.\",\n      \"method\": \"scRNA-seq, macrophage-specific KO, RNA-seq, CUT&Tag, luciferase assay, in vivo colitis model with Ap1s2 blockage\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal omics and genetic approaches with in vivo rescue\",\n      \"pmids\": [\"37015751\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZC3H12A/Regnase-1/MCPIP1 is an endoribonuclease with a PIN-like catalytic domain that recognizes stem-loop structures in the 3' UTRs of target mRNAs (including IL-6, IL-12, IL-2, c-Rel, TfR1, and many others) and cleaves them co-translationally at the ribosome/ER in a UPF1 helicase-dependent manner; its activity is dynamically regulated by IKK-mediated phosphorylation and proteasomal degradation, MALT1-mediated proteolytic cleavage at R111 upon TCR stimulation, IRAK1-mediated 14-3-3 interaction that sequesters it from mRNA, IL-17-induced Act1-TBK1/IKKi phosphorylation that releases it from the ER, and TUT7-mediated uridylation of its own mRNA; it additionally suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops to antagonize Dicer, cooperates physically with Roquin-1 through a defined interaction surface for synergistic mRNA repression, and recruits USP10 to deubiquitinate NEMO to terminate NF-κB signaling, collectively placing Regnase-1 as a master post-transcriptional brake on inflammation across innate and adaptive immune cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZC3H12A (Regnase-1/MCPIP1) is a PIN domain endoribonuclease that functions as a master post-transcriptional brake on inflammation by recognizing and cleaving stem-loop structures in the 3′ UTRs of proinflammatory mRNAs — including IL-6, IL-12, c-Rel, NFKBIZ, IL-8, C/EBPβ, and IL-17 receptor subunits — as well as viral RNAs and precursor miRNAs [PMID:22561375, PMID:26000482, PMID:22055188, PMID:23355615, PMID:27513529]. Regnase-1 acts co-translationally at the ribosome/ER in a UPF1 helicase-dependent manner, where UPF1 unwinds target stem-loops to enable cleavage, and it physically cooperates with the RNA-binding protein Roquin-1 through a defined interaction surface to synergistically repress shared inflammatory transcripts [PMID:26000482, PMID:31329944, PMID:34811541]. Its activity is dynamically controlled by IKK-mediated phosphorylation leading to proteasomal degradation upon TLR/IL-1R signaling, MALT1 paracaspase cleavage at R111 upon TCR stimulation, IRAK1-dependent 14-3-3 sequestration that blocks mRNA access, Act1–TBK1/IKKi phosphorylation that releases it from the ER upon IL-17 stimulation, and TUT7-mediated uridylation of its own mRNA, while Regnase-1 also auto-regulates by destabilizing its own transcript via a 3′ UTR stem-loop [PMID:22037600, PMID:23706741, PMID:34636324, PMID:31072819, PMID:34188032]. Beyond mRNA decay, Regnase-1 suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops in competition with Dicer, recruits the deubiquitinase USP10 to NEMO to terminate NF-κB signaling, and regulates diverse cell fates in T cells, NK cells, ILC2s, HSPCs, and intestinal epithelium through degradation of lineage-specific transcripts such as BATF, Tcf7, Gata2, and Gata3 [PMID:22055188, PMID:24270572, PMID:31827283, PMID:30842549, PMID:32978308].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing transcriptional control: identification of how ZC3H12A expression is itself induced revealed that it is an immediate-early gene driven by IL-1β through MAP kinase–Elk-1/SRF signaling at a compact promoter region.\",\n      \"evidence\": \"Promoter deletion reporters, ChIP for Elk-1/SRF, MAP kinase inhibitors in primary macrophages\",\n      \"pmids\": [\"20137095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; no genome-wide identification of additional transcription factors\", \"Upstream chromatin context not addressed\", \"Regulation by signals other than IL-1β at this promoter not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining the enzymatic mechanism and its regulation: three concurrent studies established that Regnase-1 is a bona fide endoribonuclease that degrades IL-6 mRNA, is regulated by IKK-mediated phosphorylation and proteasomal degradation forming a negative feedback loop, and additionally suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops.\",\n      \"evidence\": \"Phosphorylation/ubiquitination assays with genetic KO (IL-6 axis); in vitro pre-miRNA cleavage with domain mutagenesis and Dicer competition (miRNA axis); mRNA half-life measurements\",\n      \"pmids\": [\"22037600\", \"22055188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RNA recognition not yet resolved\", \"Identity of the full target mRNA repertoire unknown\", \"Relative contribution of mRNA decay vs. miRNA suppression in vivo unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Solving the atomic structure of the catalytic domain revealed a PIN-like RNase fold and identified both the catalytic acidic residues and a positively charged RNA-binding arm, providing the structural framework for understanding substrate recognition.\",\n      \"evidence\": \"2.0 Å X-ray crystal structure with site-directed mutagenesis abolishing RNase activity\",\n      \"pmids\": [\"22561375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No RNA-bound co-crystal structure\", \"Zinc finger and oligomerization domain structures not resolved\", \"Structural basis for stem-loop selectivity unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of MALT1-mediated cleavage at R111 upon TCR stimulation established how adaptive immune activation inactivates Regnase-1, freeing T cells from its suppressive activity on c-Rel, Ox40, and Il2 mRNAs.\",\n      \"evidence\": \"In vitro MALT1 cleavage assay with site mapping, validated in conditional KO T cells\",\n      \"pmids\": [\"23706741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of MALT1 cleavage relative to other regulatory inputs not defined\", \"Whether MALT1 cleavage products have residual function unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that Regnase-1 has broad-spectrum antiviral activity through direct RNase-mediated degradation of viral RNA expanded its role beyond endogenous mRNA regulation to innate antiviral defense.\",\n      \"evidence\": \"In vitro viral RNA cleavage, domain mutagenesis across multiple virus models (JEV, DENV, HIV, HCV, influenza)\",\n      \"pmids\": [\"23355615\", \"24191027\", \"25225661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo antiviral efficacy not demonstrated for all viruses\", \"Mechanism of viral RNA recognition specificity vs. host mRNA unclear\", \"Viral countermeasures beyond KSHV not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of USP10 recruitment to NEMO for linear polyubiquitin removal revealed a non-catalytic scaffolding function of Regnase-1 in terminating NF-κB signaling, distinct from its RNase activity.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, deubiquitination assay, siRNA knockdown, NF-κB reporter\",\n      \"pmids\": [\"24270572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP10 recruitment requires specific Regnase-1 domains beyond those tested\", \"Relevance across cell types beyond genotoxic stress context\", \"Relationship to RNase-dependent NF-κB regulation unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Spatiotemporal dissection established that Regnase-1 and Roquin regulate the same mRNAs but in distinct compartments — Regnase-1 cleaves translationally active mRNAs at the ER/ribosome via UPF1 helicase, while Roquin acts in P-bodies/stress granules — resolving how two seemingly redundant pathways cooperate.\",\n      \"evidence\": \"Subcellular fractionation, single-molecule imaging, UPF1 knockdown, polysome association\",\n      \"pmids\": [\"26000482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Regnase-1 is recruited to specific translating mRNAs vs. bulk translation unknown\", \"Stoichiometry of UPF1–Regnase-1 complex at the ribosome unresolved\", \"Whether other helicases substitute for UPF1 untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expansion of the target repertoire to IL-17 receptor subunits (Il17ra, Il17rc) and identification of 3′ UTR-independent degradation demonstrated that Regnase-1 acts as a feedback inhibitor of IL-17 signaling at multiple levels.\",\n      \"evidence\": \"MCPIP1 haploinsufficient mice, mRNA stability assay, domain mutagenesis, genetic epistasis with Il17ra KO\",\n      \"pmids\": [\"26320658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of 3′ UTR-independent target recognition not defined\", \"Whether coding-region stem-loops serve as recognition elements unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of TfR1 and PHD3 as direct Regnase-1 targets linked its endoribonuclease activity to iron homeostasis and HIF signaling, demonstrating functions far beyond cytokine mRNA decay.\",\n      \"evidence\": \"Regnase-1 KO mice with iron metabolism phenotyping, mRNA stability assay, genetic epistasis\",\n      \"pmids\": [\"28538180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether iron dysregulation contributes to immunological phenotypes of KO mice unclear\", \"Full scope of metabolic targets unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Biochemical reconstitution quantified Regnase-1's RNA binding affinity (~10 nM Kd for stem-loop substrates) and demonstrated that it oligomerizes during RNA interaction, with the zinc finger enhancing stem-loop recognition; separately, Regnase-1 was shown to suppress translation post-initiation in addition to cleaving mRNA.\",\n      \"evidence\": \"Equilibrium binding measurements, SEC for oligomerization, polysome profiling with CrPV-IRES reporter\",\n      \"pmids\": [\"29471506\", \"29743536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of oligomerization unknown\", \"Whether translational suppression is separable from cleavage in vivo unresolved\", \"Contribution of translational silencing vs. decay to target regulation not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The molecular basis of UPF1 cooperation was resolved: Regnase-1 binds SMG1-phosphorylated UPF1 via its RNase domain while an intrinsically disordered segment enhances UPF1 helicase activity, and IL-17 signaling was shown to phosphorylate Regnase-1 via Act1–TBK1/IKKi, releasing it from the ER and abolishing its function.\",\n      \"evidence\": \"Single-molecule imaging, in vitro helicase/cleavage assays, CRISPR phospho-mutant knock-in mice with in vivo inflammation models\",\n      \"pmids\": [\"31329944\", \"31072819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ER-to-cytosol translocation involves other chaperones/cofactors\", \"Structural model of UPF1–Regnase-1 complex lacking\", \"How IL-17-induced phosphorylation is reversed to restore Regnase-1 function unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genome-scale CRISPR screening in CD8+ T cells identified BATF as a key downstream mediator of Regnase-1's control of T cell fitness, establishing Regnase-1 as a checkpoint for anti-tumor T cell function.\",\n      \"evidence\": \"In vivo pooled CRISPR screen, double-KO epistasis, metabolic assays in CD8+ T cells\",\n      \"pmids\": [\"31827283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BATF mRNA is a direct cleavage substrate or indirect target not fully resolved\", \"Relative importance of multiple Regnase-1 targets in CD8+ T cell context unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Three regulatory layers were simultaneously clarified: the Roquin-1–Regnase-1 physical interaction surface was mapped (mutations cause autoimmunity), IRAK1-dependent phosphorylation at S494/S513 creates a 14-3-3 binding site that sequesters Regnase-1 from mRNA while protecting it from degradation, and TUT7-mediated uridylation of Regnase-1's own mRNA provides an additional layer of post-transcriptional control of Regnase-1 protein levels.\",\n      \"evidence\": \"Interaction surface mutagenesis and mouse autoimmunity models; interactome MS with phosphosite mutagenesis and nuclear-cytoplasmic fractionation; TUT7 KO mice with 3′-end sequencing\",\n      \"pmids\": [\"34811541\", \"34636324\", \"34188032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether 14-3-3 sequestration and ER localization are coordinated or independent regulatory modes\", \"Kinetic modeling integrating all regulatory inputs lacking\", \"Whether TUT7 regulation extends to other cell types beyond macrophages\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Therapeutic exploitation of Regnase-1's self-regulatory stem-loop was demonstrated: antisense oligonucleotides blocking the 3′ UTR stem-loop stabilize Regnase-1 mRNA, boost its protein, and suppress inflammation in ARDS and EAE models, providing proof-of-concept for pharmacological enhancement of endogenous Regnase-1.\",\n      \"evidence\": \"Antisense morpholino treatment, mRNA stability assay, intratracheal/intracranial delivery in vivo\",\n      \"pmids\": [\"35544597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety and off-target effects of ASO not assessed\", \"Whether chronic Regnase-1 elevation impairs adaptive immunity unknown\", \"Pharmacokinetics and tissue specificity of delivery not optimized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extension to NK cell biology revealed that Regnase-1 controls anti-tumor IFN-γ production through degradation of OCT2 and IκBζ mRNAs, which form a complex with NF-κB to drive Ifng transcription and CXCL16-mediated NK recruitment.\",\n      \"evidence\": \"NK cell-specific KO, mRNA target identification, co-IP of OCT2–IκBζ–NF-κB complex, tumor models\",\n      \"pmids\": [\"38821052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OCT2 mRNA is directly cleaved by Regnase-1 via canonical stem-loop mechanism not shown biochemically\", \"Interplay between NK cell and T cell Regnase-1 regulation in tumors unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for stem-loop selectivity (no RNA-bound co-crystal structure exists), the comprehensive target repertoire across cell types, how multiple phosphorylation-based regulatory inputs are temporally integrated, and whether Regnase-1's translational suppression function is mechanistically separable from its endonuclease activity in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No RNA-bound co-crystal or cryo-EM structure\", \"No single-cell-resolved target atlas across immune and non-immune lineages\", \"Quantitative kinetic model integrating IKK, MALT1, 14-3-3, TBK1, and TUT7 inputs absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 5, 6, 12, 16, 20, 25]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 12, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 8, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008953854\", \"supporting_discovery_ids\": [0, 4, 5, 12, 14, 16, 20, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3, 15, 28, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 8, 11]}\n    ],\n    \"complexes\": [\n      \"Regnase-1–UPF1 complex\",\n      \"Regnase-1–Roquin-1 complex\",\n      \"Regnase-1–14-3-3 complex\"\n    ],\n    \"partners\": [\n      \"UPF1\",\n      \"RC3H1\",\n      \"MALT1\",\n      \"USP10\",\n      \"YWHAB\",\n      \"TUT7\",\n      \"IRAK1\",\n      \"DDX3X\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway term_id. I used \"GO:0008953854\" which is incorrect. The correct Reactome ID for Metabolism of RNA is \"R-HSA-8953854\". Let me correct this:\n\n```json\n{\n  \"mechanistic_narrative\": \"ZC3H12A (Regnase-1/MCPIP1) is a PIN domain endoribonuclease that functions as a master post-transcriptional brake on inflammation by recognizing and cleaving stem-loop structures in the 3′ UTRs of proinflammatory mRNAs — including IL-6, IL-12, c-Rel, NFKBIZ, IL-8, C/EBPβ, and IL-17 receptor subunits — as well as viral RNAs and precursor miRNAs [PMID:22561375, PMID:26000482, PMID:22055188, PMID:23355615, PMID:27513529]. Regnase-1 acts co-translationally at the ribosome/ER in a UPF1 helicase-dependent manner, where UPF1 unwinds target stem-loops to enable cleavage, and it physically cooperates with the RNA-binding protein Roquin-1 through a defined interaction surface to synergistically repress shared inflammatory transcripts [PMID:26000482, PMID:31329944, PMID:34811541]. Its activity is dynamically controlled by IKK-mediated phosphorylation leading to proteasomal degradation upon TLR/IL-1R signaling, MALT1 paracaspase cleavage at R111 upon TCR stimulation, IRAK1-dependent 14-3-3 sequestration that blocks mRNA access, Act1–TBK1/IKKi phosphorylation that releases it from the ER upon IL-17 stimulation, and TUT7-mediated uridylation of its own mRNA, while Regnase-1 also auto-regulates by destabilizing its own transcript via a 3′ UTR stem-loop [PMID:22037600, PMID:23706741, PMID:34636324, PMID:31072819, PMID:34188032]. Beyond mRNA decay, Regnase-1 suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops in competition with Dicer, recruits the deubiquitinase USP10 to NEMO to terminate NF-κB signaling, and regulates diverse cell fates in T cells, NK cells, ILC2s, HSPCs, and intestinal epithelium through degradation of lineage-specific transcripts such as BATF, Tcf7, Gata2, and Gata3 [PMID:22055188, PMID:24270572, PMID:31827283, PMID:30842549, PMID:32978308].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing transcriptional control: identification of how ZC3H12A expression is itself induced revealed that it is an immediate-early gene driven by IL-1β through MAP kinase–Elk-1/SRF signaling at a compact promoter region.\",\n      \"evidence\": \"Promoter deletion reporters, ChIP for Elk-1/SRF, MAP kinase inhibitors in primary macrophages\",\n      \"pmids\": [\"20137095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; no genome-wide identification of additional transcription factors\", \"Upstream chromatin context not addressed\", \"Regulation by signals other than IL-1β at this promoter not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining the enzymatic mechanism and its regulation: three concurrent studies established that Regnase-1 is a bona fide endoribonuclease that degrades IL-6 mRNA, is regulated by IKK-mediated phosphorylation and proteasomal degradation forming a negative feedback loop, and additionally suppresses miRNA biogenesis by cleaving pre-miRNA terminal loops.\",\n      \"evidence\": \"Phosphorylation/ubiquitination assays with genetic KO (IL-6 axis); in vitro pre-miRNA cleavage with domain mutagenesis and Dicer competition (miRNA axis); mRNA half-life measurements\",\n      \"pmids\": [\"22037600\", \"22055188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RNA recognition not yet resolved\", \"Identity of the full target mRNA repertoire unknown\", \"Relative contribution of mRNA decay vs. miRNA suppression in vivo unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Solving the atomic structure of the catalytic domain revealed a PIN-like RNase fold and identified both the catalytic acidic residues and a positively charged RNA-binding arm, providing the structural framework for understanding substrate recognition.\",\n      \"evidence\": \"2.0 Å X-ray crystal structure with site-directed mutagenesis abolishing RNase activity\",\n      \"pmids\": [\"22561375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No RNA-bound co-crystal structure\", \"Zinc finger and oligomerization domain structures not resolved\", \"Structural basis for stem-loop selectivity unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of MALT1-mediated cleavage at R111 upon TCR stimulation established how adaptive immune activation inactivates Regnase-1, freeing T cells from its suppressive activity on c-Rel, Ox40, and Il2 mRNAs.\",\n      \"evidence\": \"In vitro MALT1 cleavage assay with site mapping, validated in conditional KO T cells\",\n      \"pmids\": [\"23706741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of MALT1 cleavage relative to other regulatory inputs not defined\", \"Whether MALT1 cleavage products have residual function unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that Regnase-1 has broad-spectrum antiviral activity through direct RNase-mediated degradation of viral RNA expanded its role beyond endogenous mRNA regulation to innate antiviral defense.\",\n      \"evidence\": \"In vitro viral RNA cleavage, domain mutagenesis across multiple virus models (JEV, DENV, HIV, HCV, influenza)\",\n      \"pmids\": [\"23355615\", \"24191027\", \"25225661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo antiviral efficacy not demonstrated for all viruses\", \"Mechanism of viral RNA recognition specificity vs. host mRNA unclear\", \"Viral countermeasures beyond KSHV not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of USP10 recruitment to NEMO for linear polyubiquitin removal revealed a non-catalytic scaffolding function of Regnase-1 in terminating NF-κB signaling, distinct from its RNase activity.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, deubiquitination assay, siRNA knockdown, NF-κB reporter\",\n      \"pmids\": [\"24270572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP10 recruitment requires specific Regnase-1 domains beyond those tested\", \"Relevance across cell types beyond genotoxic stress context\", \"Relationship to RNase-dependent NF-κB regulation unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Spatiotemporal dissection established that Regnase-1 and Roquin regulate the same mRNAs but in distinct compartments — Regnase-1 cleaves translationally active mRNAs at the ER/ribosome via UPF1 helicase, while Roquin acts in P-bodies/stress granules — resolving how two seemingly redundant pathways cooperate.\",\n      \"evidence\": \"Subcellular fractionation, single-molecule imaging, UPF1 knockdown, polysome association\",\n      \"pmids\": [\"26000482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Regnase-1 is recruited to specific translating mRNAs vs. bulk translation unknown\", \"Stoichiometry of UPF1–Regnase-1 complex at the ribosome unresolved\", \"Whether other helicases substitute for UPF1 untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expansion of the target repertoire to IL-17 receptor subunits (Il17ra, Il17rc) and identification of 3′ UTR-independent degradation demonstrated that Regnase-1 acts as a feedback inhibitor of IL-17 signaling at multiple levels.\",\n      \"evidence\": \"MCPIP1 haploinsufficient mice, mRNA stability assay, domain mutagenesis, genetic epistasis with Il17ra KO\",\n      \"pmids\": [\"26320658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of 3′ UTR-independent target recognition not defined\", \"Whether coding-region stem-loops serve as recognition elements unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of TfR1 and PHD3 as direct Regnase-1 targets linked its endoribonuclease activity to iron homeostasis and HIF signaling, demonstrating functions far beyond cytokine mRNA decay.\",\n      \"evidence\": \"Regnase-1 KO mice with iron metabolism phenotyping, mRNA stability assay, genetic epistasis\",\n      \"pmids\": [\"28538180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether iron dysregulation contributes to immunological phenotypes of KO mice unclear\", \"Full scope of metabolic targets unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Biochemical reconstitution quantified Regnase-1's RNA binding affinity (~10 nM Kd for stem-loop substrates) and demonstrated that it oligomerizes during RNA interaction, with the zinc finger enhancing stem-loop recognition; separately, Regnase-1 was shown to suppress translation post-initiation in addition to cleaving mRNA.\",\n      \"evidence\": \"Equilibrium binding measurements, SEC for oligomerization, polysome profiling with CrPV-IRES reporter\",\n      \"pmids\": [\"29471506\", \"29743536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of oligomerization unknown\", \"Whether translational suppression is separable from cleavage in vivo unresolved\", \"Contribution of translational silencing vs. decay to target regulation not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The molecular basis of UPF1 cooperation was resolved: Regnase-1 binds SMG1-phosphorylated UPF1 via its RNase domain while an intrinsically disordered segment enhances UPF1 helicase activity, and IL-17 signaling was shown to phosphorylate Regnase-1 via Act1–TBK1/IKKi, releasing it from the ER and abolishing its function.\",\n      \"evidence\": \"Single-molecule imaging, in vitro helicase/cleavage assays, CRISPR phospho-mutant knock-in mice with in vivo inflammation models\",\n      \"pmids\": [\"31329944\", \"31072819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ER-to-cytosol translocation involves other chaperones/cofactors\", \"Structural model of UPF1–Regnase-1 complex lacking\", \"How IL-17-induced phosphorylation is reversed to restore Regnase-1 function unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genome-scale CRISPR screening in CD8+ T cells identified BATF as a key downstream mediator of Regnase-1's control of T cell fitness, establishing Regnase-1 as a checkpoint for anti-tumor T cell function.\",\n      \"evidence\": \"In vivo pooled CRISPR screen, double-KO epistasis, metabolic assays in CD8+ T cells\",\n      \"pmids\": [\"31827283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BATF mRNA is a direct cleavage substrate or indirect target not fully resolved\", \"Relative importance of multiple Regnase-1 targets in CD8+ T cell context unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Three regulatory layers were simultaneously clarified: the Roquin-1–Regnase-1 physical interaction surface was mapped (mutations cause autoimmunity), IRAK1-dependent phosphorylation at S494/S513 creates a 14-3-3 binding site that sequesters Regnase-1 from mRNA while protecting it from degradation, and TUT7-mediated uridylation of Regnase-1's own mRNA provides an additional layer of post-transcriptional control of Regnase-1 protein levels.\",\n      \"evidence\": \"Interaction surface mutagenesis and mouse autoimmunity models; interactome MS with phosphosite mutagenesis and nuclear-cytoplasmic fractionation; TUT7 KO mice with 3′-end sequencing\",\n      \"pmids\": [\"34811541\", \"34636324\", \"34188032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether 14-3-3 sequestration and ER localization are coordinated or independent regulatory modes\", \"Kinetic modeling integrating all regulatory inputs lacking\", \"Whether TUT7 regulation extends to other cell types beyond macrophages\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Therapeutic exploitation of Regnase-1's self-regulatory stem-loop was demonstrated: antisense oligonucleotides blocking the 3′ UTR stem-loop stabilize Regnase-1 mRNA, boost its protein, and suppress inflammation in ARDS and EAE models, providing proof-of-concept for pharmacological enhancement of endogenous Regnase-1.\",\n      \"evidence\": \"Antisense morpholino treatment, mRNA stability assay, intratracheal/intracranial delivery in vivo\",\n      \"pmids\": [\"35544597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety and off-target effects of ASO not assessed\", \"Whether chronic Regnase-1 elevation impairs adaptive immunity unknown\", \"Pharmacokinetics and tissue specificity of delivery not optimized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extension to NK cell biology revealed that Regnase-1 controls anti-tumor IFN-γ production through degradation of OCT2 and IκBζ mRNAs, which form a complex with NF-κB to drive Ifng transcription and CXCL16-mediated NK recruitment.\",\n      \"evidence\": \"NK cell-specific KO, mRNA target identification, co-IP of OCT2–IκBζ–NF-κB complex, tumor models\",\n      \"pmids\": [\"38821052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OCT2 mRNA is directly cleaved by Regnase-1 via canonical stem-loop mechanism not shown biochemically\", \"Interplay between NK cell and T cell Regnase-1 regulation in tumors unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for stem-loop selectivity (no RNA-bound co-crystal structure exists), the comprehensive target repertoire across cell types, how multiple phosphorylation-based regulatory inputs are temporally integrated, and whether Regnase-1's translational suppression function is mechanistically separable from its endonuclease activity in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No RNA-bound co-crystal or cryo-EM structure\", \"No single-cell-resolved target atlas across immune and non-immune lineages\", \"Quantitative kinetic model integrating IKK, MALT1, 14-3-3, TBK1, and TUT7 inputs absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 5, 6, 12, 16, 20, 25]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 12, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 8, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 5, 12, 14, 16, 20, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3, 15, 28, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 8, 11]}\n    ],\n    \"complexes\": [\n      \"Regnase-1–UPF1 complex\",\n      \"Regnase-1–Roquin-1 complex\",\n      \"Regnase-1–14-3-3 complex\"\n    ],\n    \"partners\": [\n      \"UPF1\",\n      \"RC3H1\",\n      \"MALT1\",\n      \"USP10\",\n      \"YWHAB\",\n      \"ZCCHC11\",\n      \"IRAK1\",\n      \"DDX3X\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}