Affinage

ERI1

3'-5' exoribonuclease 1 · UniProt Q8IV48

Length
349 aa
Mass
40.1 kDa
Annotated
2026-04-28
25 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERI1 (3'hExo) is a conserved 3'-to-5' DEDDh-family exoribonuclease that plays dual housekeeping roles in ribosomal RNA maturation and replication-dependent histone mRNA metabolism, while also modulating small RNA abundance in immune cells. Its nuclease domain employs a binuclear metal cluster (D134, E136, D234, D298, H293) for hydrolytic 3'-to-5' RNA cleavage, while its SAP domain and flanking residues mediate RNA stem-loop recognition and cooperative ternary complex formation with SLBP on histone mRNA, limiting trimming to two unpaired nucleotides under steady-state conditions (PMID:15451662, PMID:23329046). ERI1 catalyzes the final 3' trimming step of 5.8S rRNA on ribosomes across species, and upon oligouridylation of histone mRNAs by TUT7, ERI1 is recruited via Lsm1-7 to degrade the stem-loop in a stepwise manner, initiating replication-dependent histone mRNA decay (PMID:18438418, PMID:23202588, PMID:36041871). Loss-of-function ERI1 missense variants cause spondyloepimetaphyseal dysplasia through defective 5.8S rRNA trimming and impaired histone mRNA degradation, with consequent failure of chondrogenic differentiation (PMID:37352860).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2004 High

    Determination of the catalytic mechanism: the crystal structure of the ERI1 nuclease domain revealed a DEDDh-family exoribonuclease fold with a binuclear metal active site, establishing the chemical basis for 3'-to-5' hydrolytic RNA cleavage and the requirement for 2'-OH and 3'-OH groups.

    Evidence 1.6 Å X-ray crystal structure with bound rAMP and Mg²⁺, validated by mutagenesis and in vitro exonuclease assays

    PMID:15451662

    Open questions at the time
    • No structural information yet on the SAP domain or full-length protein
    • Physiological RNA substrates not yet identified
  2. 2006 High

    Identification of substrate specificity and RNA-binding determinants: ERI1's SAP domain and C-terminal lysines mediate specific binding to the histone mRNA stem-loop, while the enzyme trims siRNA 3' overhangs but cannot degrade double-stranded RNA, defining its substrate scope.

    Evidence Site-directed mutagenesis separating RNA-binding from catalytic residues, in vitro binding and nuclease assays, subcellular fractionation

    PMID:16912046

    Open questions at the time
    • How ERI1 is recruited to substrates in vivo remained unknown
    • No in vivo demonstration of siRNA degradation in mammalian cells
  3. 2006 High

    Discovery of ERI1 as a negative regulator of RNAi and heterochromatic silencing: fission yeast Eri1 degrades double-stranded siRNAs, and its deletion enhances siRNA accumulation, RITS complex loading, H3-K9 methylation, and heterochromatic gene silencing.

    Evidence S. pombe eri1Δ, siRNA quantification, ChIP for H3-K9me and Swi6, in vitro dsRNA degradation

    PMID:16797182

    Open questions at the time
    • Whether mammalian ERI1 similarly regulates heterochromatic siRNA pathways was untested
    • Mechanism of dsRNA access by ERI1 in vivo unclear
  4. 2008 High

    Establishing ERI1 as the terminal 5.8S rRNA processing enzyme: mouse and C. elegans/S. pombe studies converged to show ERI1 catalyzes the final 3' trimming of 5.8S rRNA on ribosomes, with the SAP/linker domains mediating ribosome association, revealing a conserved housekeeping function.

    Evidence Ribosome co-sedimentation, in vitro rRNA processing with catalytic mutants, rescue in Eri1-deficient cells, cross-species genetics

    PMID:18438418 PMID:18438419

    Open questions at the time
    • Structural basis of ERI1–ribosome interaction not resolved
    • Whether 5.8S rRNA processing defects have physiological consequences in mammals was unclear
  5. 2012 High

    Mechanistic dissection of histone mRNA decay initiation: ERI1 trims two nucleotides from mature histone mRNA but stalls at the stem; upon oligouridylation, Lsm1-7 recognizes the oligo(U) tail and facilitates ERI1's stepwise degradation of the stem-loop, establishing ERI1 as the enzyme that initiates 3'-to-5' histone mRNA degradation.

    Evidence Eri1-deficient mouse cells accumulating oligouridylated histone mRNAs, Co-IP of Lsm1-7 with Eri1, in vitro reconstitution of stepwise degradation

    PMID:23202588

    Open questions at the time
    • How Lsm1-7 activates ERI1 catalytically on the stem-loop was structurally unresolved
    • Downstream 3'-to-5' degradation machinery after stem-loop removal not identified
  6. 2012 High

    Demonstrating ERI1's role in miRNA homeostasis and immune cell development: Eri1-deficient mouse NK and T cells show global miRNA upregulation, and Eri1 deficiency causes cell-intrinsic NK cell developmental defects, linking ERI1's exonuclease activity to immune regulation.

    Evidence Eri1 knockout mouse, small RNA profiling, ectopic expression rescue, flow cytometry for NK cell phenotyping

    PMID:22613798

    Open questions at the time
    • Whether ERI1 directly degrades mature miRNAs or acts on precursors was not resolved
    • Mechanism of sequence-independent miRNA regulation unclear
  7. 2013 High

    Structural basis of cooperative ternary complex formation: the crystal structure of SLBP–ERI1–stem-loop RNA showed that SLBP and ERI1 lack direct protein-protein contact and instead cooperate through induced RNA conformational changes, explaining how the complex limits trimming to two nucleotides.

    Evidence X-ray crystallography of the ternary complex with functional validation

    PMID:23329046

    Open questions at the time
    • How uridylation disrupts this cooperative complex to permit further degradation was not structurally captured
    • No dynamic or kinetic data on complex assembly/disassembly
  8. 2022 High

    Epistatic relationship between ERI1 and TUT7 in histone mRNA turnover: CRISPR knockouts showed ERI1 is essential for initiating 3'-side degradation on polyribosomes, while TUT7 uridylates intermediates to sustain degradation, establishing the ordered enzymatic logic of histone mRNA decay.

    Evidence CRISPR KO of ERI1 and TUT7 in human cells, synchronized cell cycle analysis, sequencing of degradation intermediates

    PMID:36041871

    Open questions at the time
    • Whether additional nucleases act redundantly with ERI1 in histone mRNA decay was not fully excluded
    • Polyribosome context of decay not structurally resolved
  9. 2023 Medium

    Uridylation differentially modulates SLBP and ERI1 binding: uridylation of histone mRNA weakens SLBP binding while maintaining ERI1 contact, providing a biophysical mechanism for the switch from steady-state trimming to processive degradation.

    Evidence Fluorescence polarization, EMSA, and molecular dynamics simulations

    PMID:37516934

    Open questions at the time
    • Computational predictions not yet validated by structural experiments
    • Single-lab study without independent replication
  10. 2023 High

    Human disease causation established: loss-of-function ERI1 missense variants cause spondyloepimetaphyseal dysplasia through impaired 5.8S rRNA trimming and histone mRNA degradation, with defective chondrogenesis in patient-derived iPSCs.

    Evidence Patient-derived cells, in vitro 5.8S rRNA and histone mRNA processing assays, iPSC chondrogenesis differentiation

    PMID:37352860

    Open questions at the time
    • Whether the skeletal phenotype is driven primarily by rRNA or histone mRNA defects is unresolved
    • No animal model recapitulating the human skeletal phenotype reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of ERI1's interaction with ribosomes during 5.8S rRNA processing, the mechanism by which Lsm1-7 activates ERI1 to degrade the stem-loop, whether ERI1 directly degrades mature miRNAs or acts on precursor forms, and the relative contributions of impaired rRNA versus histone mRNA processing to the skeletal dysplasia phenotype.
  • No full-length ERI1 structure on the ribosome
  • Lsm1-7 activation mechanism structurally unresolved
  • Direct vs. indirect miRNA regulation not distinguished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 6 GO:0003723 RNA binding 4
Localization
GO:0005829 cytosol 3 GO:0005840 ribosome 2 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 1
Partners
LSM1NPPB1PB2SLBPTUT7
Complex memberships
Lsm1-7-ERI1 complexSLBP-ERI1-stem-loop RNA ternary complex

Evidence

Reading pass · 13 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 stem-loop RNA revealed that only one base of the stem-loop is recognized specifically by SLBP, both proteins primarily recognize RNA shape, SLBP and 3'hExo have no direct protein-protein contact, and induced structural changes in the loop mediate 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 of ternary complex Science High 23329046
2004 Crystal structure of the nuclease domain of 3'hExo (ERI1) bound to rAMP with Mg2+ showed it adopts a DEDDh family alpha/beta fold with a binuclear metal cluster coordinated by D134, E136, D234, D298, and H293 acting as general base for hydrolytic RNA cleavage in the 3'→5' direction; the 2'-OH and 3'-OH groups of the substrate are required for efficient degradation. X-ray crystallography at 1.6 Å resolution; mutagenesis and in vitro exonuclease assays Journal of Molecular Biology High 15451662
2006 3'hExo (ERI1) specifically binds the 3' stem-loop of histone mRNA via its SAP domain and two lysines C-terminal to it; catalytic activity requires the DEDDh active site residues; 3'hExo trims 3' overhangs of siRNAs but cannot degrade double-stranded regions; it localizes predominantly to the cytoplasm and has only residual activity on DNA substrates. Site-directed mutagenesis, in vitro RNA binding and exonuclease assays, subcellular fractionation/localization Journal of Biological Chemistry High 16912046
2008 Mouse Eri1 associates with ribosomes and ribosomal RNA, and catalyzes the final 3' end trimming step of 5.8S rRNA; catalytically inactive Eri1 mutant fails to rescue aberrant 5.8S rRNA extension in Eri1-deficient cells; RNA binding via the SAP and linker domains promotes stable rRNA association and facilitates processing; Eri1 localizes to cytoplasm and nucleolus. Ribosome co-sedimentation, in vitro rRNA processing assay with wild-type vs. catalytic mutant, subcellular localization (immunofluorescence), rescue experiments in Eri1-deficient cells Nature Structural & Molecular Biology High 18438418
2008 ERI-1 performs 3' end processing of 5.8S rRNA in both C. elegans and S. pombe, and two protein isoforms of C. elegans ERI-1 localize to the cytoplasm with distinct functions in rRNA processing and negative regulation of RNA interference. Genetic analysis in C. elegans and S. pombe, isoform characterization, subcellular localization Nature Structural & Molecular Biology High 18438419
2012 Eri1 degrades the stem-loop of oligouridylated histone mRNAs to initiate replication-dependent decay: Eri1 trims mature histone mRNAs by two unpaired nucleotides at the 3' end but stalls at the double-stranded stem; upon oligouridylation, 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. Eri1-deficient mouse cells accumulate oligouridylated histone mRNAs with impaired degradation. Eri1-deficient mouse cell analysis, RNA sequencing, Co-IP of Lsm1-7 with Eri1, in vitro RNA degradation assays, mutagenesis Nature Structural & Molecular Biology High 23202588
2012 Eri1 regulates miRNA homeostasis in mouse lymphocytes; Eri1-deficient NK and T cells display a global, sequence-independent 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 and Ly49 receptor acquisition. Eri1 knockout mouse, small RNA profiling, reconstitution by ectopic expression, flow cytometry for NK cell phenotype Blood High 22613798
2006 Fission yeast Eri1 specifically degrades double-stranded siRNAs through two functional domains, represses accumulation of cellular siRNAs in vivo, and deletion of eri1+ increases siRNAs associated with the RITS complex, enhancing heterochromatic silencing with increased H3-K9 methylation and Swi6 protein levels. Eri1 deletion in S. pombe, siRNA quantification, ChIP for H3-K9 methylation and Swi6, in vitro dsRNA degradation assays Current Biology High 16797182
2022 3'hExo (ERI1) is essential for initiating histone mRNA degradation on polyribosomes at the 3' side of the stem-loop; 3'hExo cooperates with TUT7 (TENT3B/ZCCHC6) to both maintain histone mRNA length during S-phase and degrade it at S-phase end; knockout of 3'hExo prevents initiation of 3'→5' degradation and stabilizes histone mRNA, while TUT7 knockout prevents uridylation of degradation intermediates slowing degradation. CRISPR knockout of TUT7 and 3'hExo in human cells, synchronized cell analysis, RNA sequencing of degradation intermediates RNA High 36041871
2020 ERI1 interacts with the PB2, PB1, and NP components of influenza A viral ribonucleoproteins in an RNA-dependent manner, and both the RNA binding and exonuclease activities of ERI1 are required to promote influenza A virus mRNA transcription; during infection, SLBP and histone mRNAs co-purify with vRNPs alongside ERI1, suggesting ERI1 is recruited as part of the histone pre-mRNA processing complex in the nucleus. Interactomics/Co-IP, siRNA silencing, viral transcription assay, ERI1 activity mutants Nucleic Acids Research Medium 32960265
2023 ERI1 missense variants identified in patients with spondyloepimetaphyseal dysplasia cause loss of exoribonuclease activity, leading to defective trimming of the 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. Patient-derived cells, in vitro 5.8S rRNA processing assay, histone mRNA degradation assay, iPSC chondrogenesis differentiation American Journal of Human Genetics High 37352860
2023 Uridylation of the histone mRNA stem-loop weakens binding interactions with SLBP while maintaining interactions with 3'hExo (ERI1); uridylation allows 3'hExo to maintain contact with the stem-loop after partial degradation and disrupts key base pairs in partially degraded histone mRNA intermediates. Fluorescence polarization, EMSA, 1-µs molecular dynamics simulations RNA Biology Medium 37516934
2017 Drosophila Snipper (ERI1 homolog) directly interacts with histone mRNA; its depletion causes drastic reduction in histone transcript levels, suggesting Snp protects histone mRNA 3'-ends from degradation; Snp perturbation leads to larval arrest and tissue-specific developmental abnormalities. RNA immunoprecipitation, RNAi knockdown, developmental phenotype analysis in Drosophila FEBS Letters Medium 28626879

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 65 23202588
2008 The exonuclease ERI-1 has a conserved dual role in 5.8S rRNA processing and RNAi. Nature structural & molecular biology 59 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
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
2014 Eri1: a conserved enzyme at the crossroads of multiple RNA-processing pathways. Trends in genetics : TIG 28 24929628
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 6 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
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 Knockouts of TUT7 and 3'hExo show that they cooperate in histone mRNA maintenance and degradation. RNA (New York, N.Y.) 3 36041871
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
2017 Snipper, an Eri1 homologue, affects histone mRNA abundance and is crucial for normal Drosophila melanogaster development. FEBS letters 2 28626879
2024 The ER-Resident Ras Inhibitor 1 (Eri1) of Candida albicans Inhibits Hyphal Morphogenesis via the Ras-Independent cAMP-PKA Pathway. ACS infectious diseases 1 39119676
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