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Showing ERI1 — 3'HEXO is a alias.

ERI1

3'-5' exoribonuclease 1 · UniProt Q8IV48

Length
349 aa
Mass
40.1 kDa
Annotated
2026-06-09
25 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERI1 (3'hExo/THEX1) is a DEDDh-family 3'-to-5' exoribonuclease that catalyzes multiple RNA maturation and decay reactions through a binuclear metal active site in which four acidic residues (D134, E136, D234, D298) coordinate two Mg2+ ions and H293 serves as the catalytic general base (PMID:15451662). Its catalytic activity depends on 2' and 3' hydroxyls at the terminal nucleotide, is RNA-specific with negligible activity on DNA, and substrate engagement requires the SAP domain and adjacent lysines (PMID:16912046). In ribosome biogenesis, ERI1 performs the final 3'-end trimming of 5.8S rRNA, associating with ribosomes and rRNA through RNA-binding residues in its SAP and linker domains; loss of catalytic activity produces aberrantly extended 5.8S rRNA (PMID:18438418, PMID:18438419). In histone mRNA metabolism, ERI1 binds the 3' stem-loop cooperatively with SLBP without direct protein-protein contact, instead being coordinated through RNA loop conformational changes, with the 3' flanking sequence positioned in its active site (PMID:23329046); it trims histone mRNA to a few nucleotides past the stem-loop and then, following TUT7/TENT3B-mediated uridylation and recruitment of the Lsm1-7 heptamer to the oligo(U) tail, degrades into the stem-loop to initiate replication-dependent histone mRNA decay (PMID:23202588, PMID:36041871). ERI1 also negatively regulates RNA interference: it degrades siRNA 3' overhangs but not duplex regions and represses siRNA accumulation and RNAi-mediated heterochromatin assembly (PMID:16912046, PMID:16797182), and in mammalian lymphocytes it controls global miRNA homeostasis, with its loss elevating miRNA levels and impairing NK cell development and antiviral immunity (PMID:22613798). Biallelic loss-of-function ERI1 variants impair 5.8S rRNA processing and histone mRNA decay and cause defective human skeletal patterning and chondrogenesis (PMID:37352860).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2004 High

    Established the catalytic chemistry of ERI1 by resolving how its active site organizes metal-dependent RNA hydrolysis, defining it as a DEDDh exonuclease.

    Evidence X-ray crystallography of the nuclease domain with rAMP and Mg2+ at 1.6 Å resolution

    PMID:15451662

    Open questions at the time
    • Structure captured an isolated nuclease domain without bound physiological substrate
    • Did not address how substrate specificity for histone mRNA versus rRNA is achieved
  2. 2006 High

    Defined ERI1 substrate preferences and domain requirements, showing it is an RNA-specific exonuclease that engages histone mRNA 3' ends and siRNA overhangs via the SAP domain.

    Evidence Active-site and RNA-binding mutagenesis with in vitro RNA/DNA degradation and binding assays plus localization

    PMID:16912046

    Open questions at the time
    • In vitro substrate binding did not establish in vivo function for each substrate
    • How activity is restrained on cellular targets not resolved
  3. 2006 High

    Demonstrated that ERI1 negatively regulates RNAi in vivo by degrading siRNAs and limiting heterochromatin assembly, linking the exonuclease to small-RNA pathway suppression.

    Evidence Genetic deletion in S. pombe with siRNA quantification, ChIP for H3-K9 methylation, and RITS co-IP

    PMID:16797182

    Open questions at the time
    • Mechanism of siRNA selection in vivo not detailed
    • Generality to mammalian small-RNA regulation not addressed here
  4. 2008 High

    Identified ERI1's role in ribosome biogenesis as the enzyme performing the terminal 3' trimming of 5.8S rRNA, conserved from yeast to mammals.

    Evidence Eri1-deficient mice and C. elegans/S. pombe genetics, in vitro reconstitution with catalytic mutants, subcellular fractionation, and SAP/linker mutagenesis

    PMID:18438418 PMID:18438419

    Open questions at the time
    • How ERI1 is recruited to pre-ribosomes mechanistically unclear
    • Functional separation of rRNA versus RNAi roles (isoform-specific in C. elegans) not fully resolved in mammals
  5. 2012 High

    Resolved how cell-cycle-coupled histone mRNA decay is initiated, showing ERI1 stalls at the stem and is licensed to degrade it only after oligouridylation recruits Lsm1-7.

    Evidence Mouse Eri1 knockout cells, biochemical analysis of mRNA intermediates, and Lsm1-7 co-immunoprecipitation

    PMID:23202588

    Open questions at the time
    • Direct contacts between Lsm1-7 and ERI1 not structurally defined
    • TUTase responsible for uridylation not identified in this study
  6. 2012 High

    Extended ERI1 function to mammalian miRNA homeostasis and immune development, showing it sets global miRNA abundance in lymphocytes sequence-independently.

    Evidence Eri1-/- mice with small RNA sequencing, ectopic Eri1 rescue in T cells, and in vivo MCMV infection assays

    PMID:22613798

    Open questions at the time
    • Whether ERI1 acts directly on mature miRNAs or via trimming intermediates not fully separated
    • Molecular basis of NK developmental defect downstream of miRNA changes unclear
  7. 2013 High

    Explained the structural basis for cooperative histone mRNA recognition, showing SLBP and ERI1 cooperate through RNA conformational changes rather than direct protein contact, which limits trimming.

    Evidence X-ray crystallography of the SLBP–3'hExo–stem-loop ternary complex

    PMID:23329046

    Open questions at the time
    • Static structure does not capture transition to active degradation
    • Does not show how the complex is destabilized to permit decay
  8. 2020 Medium

    Linked ERI1 to viral biology, showing it is recruited via the histone processing machinery to influenza vRNPs and is required for viral mRNA transcription.

    Evidence Interactomics, RNase-sensitive co-IP with PB2/PB1/NP, siRNA silencing, and viral transcription assays

    PMID:32960265

    Open questions at the time
    • Single lab and not independently replicated
    • Whether ERI1 catalysis acts on viral RNA or on host RNA recruited to vRNPs unresolved
  9. 2022 High

    Established genetic epistasis showing ERI1 initiates polyribosome-associated histone mRNA degradation and cooperates with TUT7/TENT3B, which uridylates intermediates.

    Evidence CRISPR knockout of 3'hExo and TUT7, synchronized cell-cycle experiments, RNA-seq and Northern blot of mRNA intermediates

    PMID:36041871

    Open questions at the time
    • Order and coupling of ERI1 trimming and TUT7 uridylation at single-molecule level not defined
    • Regulation of the switch from maintenance to degradation during S-phase exit unclear
  10. 2023 Medium

    Defined the biophysics of the decay transition, showing uridylation weakens SLBP binding while ERI1 retains contact with partially degraded intermediates.

    Evidence Fluorescence polarization, EMSA, and 1-µs molecular dynamics simulations

    PMID:37516934

    Open questions at the time
    • Single lab; affinity measurements not validated by in-cell kinetics
    • MD predictions of base-pair disruption not structurally confirmed
  11. 2023 Medium

    Connected ERI1 RNA metabolism to human disease, showing biallelic loss-of-function variants impair rRNA and histone mRNA processing and cause skeletal patterning defects.

    Evidence Patient-derived iPSC chondrogenesis, biochemical assays of 5.8S rRNA and histone mRNA in patient cells, genotype-phenotype analysis

    PMID:37352860

    Open questions at the time
    • Single study; tissue-specificity of skeletal phenotype mechanistically unexplained
    • Whether rRNA or histone mRNA defect (or both) drives chondrogenesis failure not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ERI1's distinct substrate roles (5.8S rRNA, histone mRNA, siRNA/miRNA) are partitioned and regulated within a single cell remains unresolved.
  • No structural model of ERI1 engaged with rRNA or with the full decay machinery
  • Recruitment determinants directing ERI1 to each substrate class not defined
  • Mechanism coupling its activity to cell-cycle and immune signaling unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0003723 RNA binding 3 GO:0016787 hydrolase activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
LSM1-7SLBPTUT7

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Crystal structure of the ternary complex of human SLBP RNA binding domain, human 3'hExo (ERI1), and a 26-nucleotide histone mRNA stem-loop RNA revealed that SLBP and 3'hExo have no direct protein-protein contact with each other; instead, induced structural changes in the loop of the stem-loop RNA mediate their cooperative binding. The 3' flanking sequence is positioned in the 3'hExo active site, but the ternary complex limits the extent of trimming. X-ray crystallography (crystal structure of ternary complex) Science High 23329046
2012 Eri1 trims mature histone mRNAs by two unpaired nucleotides at the 3' end but stalls at the double-stranded stem. Upon oligouridylation of histone mRNA, the Lsm1-7 heteroheptamer recognizes the oligo(U) tail and interacts with Eri1, enabling Eri1's catalytic activity to degrade the stem-loop in a stepwise manner, initiating replication-dependent histone mRNA decay. Mouse cell genetic knockout (Eri1-deficient cells), biochemical analysis of mRNA intermediates, co-immunoprecipitation of Lsm1-7 with Eri1 Nature structural & molecular biology High 23202588
2008 Mouse Eri1 associates with ribosomes and ribosomal RNA, and catalyzes the final 3' end trimming step of 5.8S rRNA processing. Ribosomes from Eri1-deficient mice contain aberrantly extended 5.8S rRNA, and catalytically active Eri1 (but not a catalytically inactive mutant) restores wild-type 5.8S rRNA in vitro and in cells. Eri1 localizes to the cytoplasm and nucleus, with enrichment in the nucleolus. RNA binding residues in the SAP and linker domains promote stable association with rRNA. Genetic knockout (Eri1-deficient mice), in vitro reconstitution with catalytic mutant, subcellular fractionation/localization, mutagenesis of SAP and linker domains Nature structural & molecular biology High 18438418
2008 C. elegans ERI-1 and S. pombe Eri1 perform 3' end processing of 5.8S rRNA. Two protein isoforms of C. elegans ERI-1 are localized to the cytoplasm, and each isoform has distinct functions in rRNA processing versus negative regulation of RNA interference. Genetic analysis in C. elegans and S. pombe, isoform-specific functional assays, subcellular localization Nature structural & molecular biology High 18438419
2006 3'hExo (ERI1) is a DEDDh family 3' exonuclease. Specific RNA binding requires the SAP domain and two lysines C-terminal to it. 3'hExo binds with highest affinity to the wild-type 3' end of histone mRNA. It has negligible exonuclease activity on DNA substrates. It removes 3' overhangs of siRNAs but cannot degrade the double-stranded region. The protein localizes mostly to the cytoplasm. Efficient degradation requires 2' and 3' hydroxyl groups at the last nucleotide. Mutagenesis of catalytic and RNA-binding residues, in vitro RNA/DNA degradation assays, RNA binding assays, subcellular localization The Journal of biological chemistry High 16912046
2004 Crystal structure of the nuclease domain of 3'hExo complexed with rAMP and Mg2+ at 1.6 Å resolution. The active site contains four acidic residues (D134, E136, D234, D298) coordinating a binuclear Mg2+ cluster, and H293 as a potential general base, consistent with DEDDh exonuclease family mechanism for 3'→5' hydrolytic cleavage of RNA. X-ray crystallography (1.6 Å resolution), metal coordination analysis Journal of molecular biology High 15451662
2006 S. pombe Eri1 specifically degrades double-stranded siRNAs through two functional domains and represses accumulation of cellular siRNAs in vivo. Deletion of eri1+ causes increased siRNAs associated with the RITS complex, enhanced heterochromatic silencing, increased histone H3-K9 methylation, and elevated Swi6 protein levels, demonstrating that Eri1 negatively regulates RNAi-mediated heterochromatin assembly. Genetic deletion in S. pombe, chromatin immunoprecipitation (H3-K9 methylation), siRNA quantification, RITS complex co-immunoprecipitation Current biology High 16797182
2012 Eri1 regulates microRNA homeostasis in mouse lymphocytes in a sequence-independent manner. Both NK and T cells deficient in Eri1 display a global increase in miRNA abundance. Ectopic Eri1 expression rescues defective miRNA expression in mature Eri1-deficient T cells. Eri1 deficiency causes cell-intrinsic defects in NK cell development, delayed Ly49 receptor acquisition, and impaired virus-specific expansion during MCMV infection. Genetic knockout (Eri1-/- mice), small RNA sequencing, ectopic Eri1 reconstitution in T cells, in vivo viral infection assays Blood High 22613798
2022 3'hExo (ERI1) is essential for initiating histone mRNA degradation on polyribosomes by degrading into the 3' side of the stem-loop. Knockout of 3'hExo prevents initiation of 3'→5' degradation and stabilizes histone mRNA. 3'hExo cooperates with the specific TUTase TENT3B/TUT7 (ZCCHC6): 3'hExo trims histone mRNA to 3 nt after the stem-loop and maintains mRNA length during S-phase, while TUT7 uridylates degradation intermediates to promote degradation. CRISPR knockout of 3'hExo and TUT7, synchronized cell cycle experiments, RNA sequencing and Northern blotting of histone mRNA intermediates RNA High 36041871
2020 ERI1 interacts with the PB2, PB1, and NP components of influenza A virus ribonucleoproteins (vRNPs) and is required for viral mRNA transcription. The protein-protein interaction is RNA-dependent. Both the RNA-binding and exonuclease activities of ERI1 are required to promote influenza A virus transcription. During infection, SLBP and histone mRNAs co-purify with vRNPs alongside ERI1, indicating ERI1 is recruited as part of the histone pre-mRNA processing complex in the nucleus. Stringent interactomics screening, siRNA silencing, co-immunoprecipitation (RNase sensitivity tested), functional viral transcription assays Nucleic acids research Medium 32960265
2023 ERI1 missense variants causing loss of exoribonuclease activity lead to defective trimming of 5.8S rRNA 3' end and decreased degradation of replication-dependent histone mRNAs. Patient-derived iPSCs showed impaired in vitro chondrogenesis with downregulation of skeletal patterning genes, establishing ERI1 RNA metabolism function as required for human skeletal patterning and chondrogenesis. Patient-derived iPSC differentiation (chondrogenesis), biochemical assay of 5.8S rRNA processing and histone mRNA levels in patient cells, genotype-phenotype analysis of bi-allelic ERI1 variants American journal of human genetics Medium 37352860
2023 Uridylation of the histone mRNA stem-loop weakens SLBP binding affinity but allows 3'hExo to maintain contact with the stem-loop after partial degradation. Fluorescence polarization and EMSA showed both SLBP and 3'hExo can bind uridylated/partially degraded stem-loop intermediates with lower affinity. Molecular dynamics simulations revealed that uridylation disrupts key base pairs in partially degraded histone mRNA and that SLBP dephosphorylation (TPNK motif) further weakens RNA-protein interactions. Fluorescence polarization, EMSA, 1-µs molecular dynamics simulations (AMBER/NAMD force field) RNA biology Medium 37516934

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Structure of histone mRNA stem-loop, human stem-loop binding protein, and 3'hExo ternary complex. Science (New York, N.Y.) 102 23329046
2012 Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay. Nature structural & molecular biology 66 23202588
2008 The exonuclease ERI-1 has a conserved dual role in 5.8S rRNA processing and RNAi. Nature structural & molecular biology 60 18438419
2012 Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviral function. Blood 57 22613798
2008 Mouse Eri1 interacts with the ribosome and catalyzes 5.8S rRNA processing. Nature structural & molecular biology 55 18438418
2006 Characterization of 3'hExo, a 3' exonuclease specifically interacting with the 3' end of histone mRNA. The Journal of biological chemistry 48 16912046
2006 Conserved ribonuclease, Eri1, negatively regulates heterochromatin assembly in fission yeast. Current biology : CB 46 16797182
2004 Crystallographic structure of the nuclease domain of 3'hExo, a DEDDh family member, bound to rAMP. Journal of molecular biology 40 15451662
2003 A novel Ras inhibitor, Eri1, engages yeast Ras at the endoplasmic reticulum. Molecular and cellular biology 33 12832483
2014 Eri1: a conserved enzyme at the crossroads of multiple RNA-processing pathways. Trends in genetics : TIG 29 24929628
2006 Genetic and biochemical characterization of Drosophila Snipper: A promiscuous member of the metazoan 3'hExo/ERI-1 family of 3' to 5' exonucleases. RNA (New York, N.Y.) 29 17135487
2017 Homozygous microdeletion of the ERI1 and MFHAS1 genes in a patient with intellectual disability, limb abnormalities, and cardiac malformation. American journal of medical genetics. Part A 10 28488351
2020 Influenza A virus co-opts ERI1 exonuclease bound to histone mRNA to promote viral transcription. Nucleic acids research 7 32960265
2016 Reserpine requires the D2-type receptor, dop-3, and the exoribonuclease, eri-1, to extend the lifespan in C. elegans. Journal of biosciences 7 27966489
2007 esiRNA to eri-1 and adar-1 genes improving high doses of c-myc-directed esiRNA effect on mouse melanoma growth inhibition. Biochemical and biophysical research communications 6 17658462
2016 ERIL1, the plant homologue of ERI-1, is involved in the processing of chloroplastic rRNAs. The Plant journal : for cell and molecular biology 5 27531275
2022 Knockouts of TUT7 and 3'hExo show that they cooperate in histone mRNA maintenance and degradation. RNA (New York, N.Y.) 4 36041871
2016 Anti-Ephrin Type-B Receptor 2 (EphB2) and Anti-Three Prime Histone mRNA EXonuclease 1 (THEX1) Autoantibodies in Scleroderma and Lupus. PloS one 4 27617966
2014 A pre- and co-knockdown of RNAseT enzyme, Eri-1, enhances the efficiency of RNAi induced gene silencing in Caenorhabditis elegans. PloS one 4 24475317
2023 Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans. American journal of human genetics 3 37352860
2022 ERI1: A case report of an autosomal recessive syndrome associated with developmental delay and distal limb abnormalities. American journal of medical genetics. Part A 3 36208065
2024 The ER-Resident Ras Inhibitor 1 (Eri1) of Candida albicans Inhibits Hyphal Morphogenesis via the Ras-Independent cAMP-PKA Pathway. ACS infectious diseases 2 39119676
2017 Snipper, an Eri1 homologue, affects histone mRNA abundance and is crucial for normal Drosophila melanogaster development. FEBS letters 2 28626879
2025 Congenital Bone Disorders Associated with ERI1-Mediated RNA Metabolism Dysfunction: Spondylo-Epi-Metaphyseal Dysplasia Guo-Campeau Type and Beyond. Current osteoporosis reports 0 39945916
2023 Uridylation of the histone mRNA stem-loop weakens binding interactions with SLBP while maintaining interactions with 3'hExo. RNA biology 0 37516934

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