Affinage

LSM8

U6 snRNA-associated Sm-like protein LSm8 · UniProt O95777

Length
96 aa
Mass
10.4 kDa
Annotated
2026-06-10
22 papers in source corpus 10 papers cited in narrative 10 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

LSM8 is the defining subunit of the nuclear Lsm2-8 heteroheptameric ring, which binds and stabilizes spliceosomal U6 snRNA and is essential for the early steps of U6 snRNP assembly (PMID:9857199, PMID:15075370). Within the ring, subunits arrange in the order Lsm3-2-8-4-7-5-6, and Lsm8 directly engages the 3'-oligo(U) end of U6 snRNA, contributing uracil-base recognition through a conserved asparagine residue as part of a modular four-uridine binding interface (PMID:24240276). The ring specifically recognizes post-transcriptionally 3'-end-processed U6 snRNA and is positioned adjacent to the chaperone active site of Prp24 in the assembled U6 snRNP (PMID:29717126). Genetic analysis establishes that support of U6 snRNA biogenesis is the sole essential function of yeast Lsm8: both lethal deletion and overexpression bypass experiments show the requirement for LSM8 is relieved by overexpression of U6 snRNA (or Prp24) (PMID:11333229, PMID:29615482). The N-terminal region of Lsm8 promotes nuclear retention of the Lsm2-8 complex, distinguishing it from cytoplasmic Lsm1 (PMID:19490016). In metazoan systems, the LSM2-8 complex extends beyond snRNP function: in C. elegans it cooperates with the 5'-3' exoribonuclease XRN-2 to degrade RNAs at H3K27me3-marked heterochromatic loci (PMID:32350050), and human LSM8 promotes Hepatitis B virus RNA production in an m6A-dependent manner (PMID:36016928).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 High

    Established that Lsm8 is a required factor for U6 snRNP, answering whether this Sm-like protein has a defined role in spliceosomal RNA metabolism.

    Evidence Yeast genetics with lsm8-1 mutant and Northern analysis of U6 snRNA levels

    PMID:9857199

    Open questions at the time
    • Did not define the molecular architecture of the complex
    • Mechanism of U6 stabilization unresolved
  2. 2001 High

    Showed that U6 snRNA biogenesis is the single essential function of Lsm8 and placed it physically within the Lsm2-8 ring via contacts with Lsm2 and Lsm4.

    Evidence Allele-specific genetic suppression, U6 overexpression rescue, and immunoprecipitation in yeast

    PMID:11333229

    Open questions at the time
    • No structural detail of subunit arrangement
    • Did not address how the ring discriminates U6 from other RNAs
  3. 2004 High

    Distinguished the Lsm8-containing nuclear Lsm2-8 complex (U6 binding) from a separate Lsm2-7 complex, defining Lsm8 as the subunit conferring U6/spliceosomal specificity and nuclear function.

    Evidence Co-IP, glycerol gradient sedimentation, and in vitro reconstitution in yeast

    PMID:15075370

    Open questions at the time
    • Did not resolve the structural basis of RNA target discrimination
    • Localization determinants not mapped
  4. 2009 Medium

    Identified the Lsm8 N-terminus as a determinant of nuclear retention, addressing why the Lsm2-8 complex accumulates in the nucleus unlike cytoplasmic Lsm1 complexes.

    Evidence Domain-swap and hybrid Lsm1/Lsm8 mutants analyzed by fluorescence microscopy in budding yeast

    PMID:19490016

    Open questions at the time
    • No single sufficient localization domain identified
    • Trafficking machinery interacting with the N-terminus unknown
    • Single-lab microscopy evidence
  5. 2013 High

    Resolved the atomic architecture, establishing the subunit order and the modular base-specific recognition of U6 3'-oligo(U) by Lsm8 via a conserved asparagine.

    Evidence 2.8 Å X-ray crystal structure of Lsm2-8 bound to U6 3' end with biochemical binding assays

    PMID:24240276

    Open questions at the time
    • Did not show the ring in the context of the full U6 snRNP
    • Did not address recognition of processed vs unprocessed 3' ends in vivo
  6. 2018 High

    Placed the Lsm2-8 ring within the assembled U6 snRNP adjacent to the Prp24 chaperone and demonstrated specificity for 3'-end-processed U6 snRNA.

    Evidence Cryo-EM structure of the yeast U6 snRNP

    PMID:29717126

    Open questions at the time
    • Functional consequence of Lsm8 C-terminal homology to Lsm1 untested
    • Dynamics of Prp24-Lsm2-8 coupling unresolved
  7. 2018 High

    Confirmed genetically that supporting U6 snRNA is the only essential function of Lsm8 and the other Lsm2-8 subunits, by rescuing lethal deletions with U6 or Prp24 overexpression.

    Evidence Yeast deletion rescue and alanine-scanning mutagenesis of RNA-binding/interface residues

    PMID:29615482

    Open questions at the time
    • Does not exclude non-essential moonlighting roles
    • Metazoan-specific functions not addressed
  8. 2020 Medium

    Extended Lsm8/LSM2-8 function beyond splicing to chromatin-linked RNA turnover, showing cooperation with XRN-2 to degrade RNAs at H3K27me3-marked loci.

    Evidence C. elegans genetic screen, reporter and RNA-stabilization assays, and H3K27me3 ChIP

    PMID:32350050

    Open questions at the time
    • Direct physical interaction between LSM2-8 and XRN-2 not structurally defined
    • How the complex is recruited to Polycomb loci unknown
    • Conservation to mammals untested
  9. 2022 Medium

    Implicated human LSM8 in viral RNA metabolism, linking it to m6A methylation of HBV pregenomic RNA.

    Evidence siRNA knockdown of LSM8 in an HBV replication model with MeRIP and viral RNA quantification

    PMID:36016928

    Open questions at the time
    • Whether LSM8 acts directly on viral RNA or via the m6A machinery unresolved
    • No reciprocal or structural validation
    • Single-lab knockdown evidence
  10. 2025 High

    Defined the structural determinant (SC1-SC3 interaction) that distinguishes Lsm-type from Sm-type ring assembly and RNA-binding mode.

    Evidence Protein engineering, in vitro reconstitution of hybrid rings, and functional RNA-binding assays

    PMID:40433979

    Open questions at the time
    • In vivo relevance of engineered conversions not tested
    • Does not address regulation of ring assembly in cells

Open questions

Synthesis pass · forward-looking unresolved questions
  • How metazoan LSM8-containing complexes are recruited to and act at chromatin and viral RNA targets, and whether these functions are mechanistically distinct from canonical U6 stabilization, remains unresolved.
  • No structural model of LSM2-8 with XRN-2 or m6A machinery
  • Recruitment mechanism to H3K27me3 loci unknown
  • Direct vs indirect role in viral m6A methylation unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0005198 structural molecule activity 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 4
Partners
LSM2LSM4PRP24XRN-2
Complex memberships
Lsm2-8 complexU6 snRNP

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Lsm8p is a novel component of the yeast U6 snRNP; lsm8-1 mutant cells have drastically reduced levels of mature U6 snRNP, implicating Lsm8p as a key component in the early steps of U6 snRNP assembly. Yeast genetics (lsm8-1 mutant isolation), Northern blot analysis of U6 snRNA levels The EMBO journal High 9857199
2001 Lsm2p and Lsm4p contact Lsm8p within the Lsm2-8 ring; LSM2 and LSM4 act as allele-specific low-copy suppressors of lsm8 mutations. Overexpression of U6 snRNA bypasses the requirement for LSM8, indicating that the only essential function of LSM8 is in U6 RNA biogenesis or function. Yeast genetic suppression analysis, overexpression rescue experiments, immunoprecipitation Genetics High 11333229
2004 The Lsm2-8 complex (containing Lsm8) binds and stabilizes spliceosomal U6 snRNA in the nucleus, while a separate Lsm2-7 complex (lacking Lsm8) associates with the snoRNA snR5 and is present in nucleoli. Immunoprecipitation, glycerol gradient sedimentation, in vitro reconstitution of Lsm binding to snR5 Molecular biology of the cell High 15075370
2009 The N-terminal region of Lsm8p contributes to nuclear accumulation of the Lsm2-8 complex; no single domain is essential or sufficient for localization, but the shorter Lsm8p N-terminus (relative to Lsm1p) promotes nuclear retention of the complex. Analysis of mutant and hybrid Lsm1/Lsm8 proteins by fluorescence microscopy in budding yeast The FEBS journal Medium 19490016
2013 Crystal structure of the heptameric Lsm2-8 complex bound to the 3' end of U6 snRNA at 2.8 Å resolution reveals that Lsm proteins arrange in the order Lsm3-2-8-4-7-5-6. Lsm8 directly contacts the U6 snRNA 3' end: four uridine nucleotides are modularly recognized by Lsm3, Lsm2, Lsm8, and Lsm4, with uracil-base specificity conferred by a conserved asparagine residue in each subunit. X-ray crystallography (2.8 Å), biochemical binding assays Nature High 24240276
2018 Cryo-EM structure of the yeast U6 snRNP reveals that the Lsm2-8 heteroheptameric ring is positioned in close proximity to the chaperone active site of Prp24, and that the Lsm2-8 ring specifically recognizes post-transcriptionally 3'-end-processed U6 snRNA. The C-terminal region of Lsm8 shows unanticipated homology to cytoplasmic Lsm1. Cryo-EM structural determination of U6 snRNP from Saccharomyces cerevisiae Nature communications High 29717126
2018 Lethal deletions of LSM8 (as well as lsm2Δ, lsm3Δ, lsm4Δ, lsm5Δ) are rescued by overexpression of U6 snRNA or overexpression of the U6 snRNP protein Prp24, demonstrating that supporting U6 snRNA is the only essential function of the yeast Lsm2-8 proteins including Lsm8. Yeast genetics: gene deletion rescue by high-copy U6 snRNA or Prp24 overexpression; alanine scanning mutagenesis of RNA-binding and intersubunit interface residues RNA (New York, N.Y.) High 29615482
2020 In C. elegans, the LSM2-8 complex (including lsm-8) contributes to repression of Polycomb/H3K27me3-marked heterochromatic loci; loss of lsm-8 causes selective mRNA stabilization at these loci and a localized drop in H3K27me3 levels. LSM2-8 works cooperatively with the 5'-3' exoribonuclease XRN-2 to degrade these RNAs. C. elegans genetic screen, reporter assays, RNA stabilization assays, chromatin immunoprecipitation (H3K27me3) Cold Spring Harbor symposia on quantitative biology Medium 32350050
2022 LSM8 (the unique subunit of the nuclear Lsm2-8 complex) promotes Hepatitis B virus RNA production; siRNA-mediated knockdown of LSM8 reduced viral RNA levels in a manner dependent on N6-adenosine methylation (m6A) of the epsilon stem-loop at the 5' end of pre-Core/pregenomic RNA. MeRIP assays showed that LSM8 knockdown reduced viral RNA m6A methylation. siRNA knockdown of LSM8 in HBV replication model, MeRIP (methylated RNA immunoprecipitation), quantitative viral RNA analysis Frontiers in immunology Medium 36016928
2025 Interconversion experiments between Sm and Lsm2-8 rings reveal that the SC1-SC3 interaction (between Lsm2/3 and Lsm8/4 subcomplexes) is a key determinant distinguishing Lsm-type from Sm-type ring assembly and RNA-binding mode. Strengthening SC1-SC3 interaction converted the Sm ring into an Lsm-type ring; weakening it plus introducing RNA-binding mutations converted Lsm2-8 into an Sm-type ring. Protein engineering/mutagenesis, in vitro reconstitution of hybrid rings, functional RNA-binding assays Nucleic acids research High 40433979

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 A role for the yeast La protein in U6 snRNP assembly: evidence that the La protein is a molecular chaperone for RNA polymerase III transcripts. The EMBO journal 178 9857199
2011 3' processing of eukaryotic precursor tRNAs. Wiley interdisciplinary reviews. RNA 116 21572561
2013 Crystal structures of the Lsm complex bound to the 3' end sequence of U6 small nuclear RNA. Nature 86 24240276
2018 The Evf2 Ultraconserved Enhancer lncRNA Functionally and Spatially Organizes Megabase Distant Genes in the Developing Forebrain. Molecular cell 67 30146317
2001 Multiple functional interactions between components of the Lsm2-Lsm8 complex, U6 snRNA, and the yeast La protein. Genetics 65 11333229
2021 Chronic mild stress-induced protein dysregulations correlated with susceptibility and resiliency to depression or anxiety revealed by quantitative proteomics of the rat prefrontal cortex. Translational psychiatry 45 33627638
2014 RNA binding by Hfq and ring-forming (L)Sm proteins: a trade-off between optimal sequence readout and RNA backbone conformation. RNA biology 39 24828406
2004 An Lsm2-Lsm7 complex in Saccharomyces cerevisiae associates with the small nucleolar RNA snR5. Molecular biology of the cell 37 15075370
2018 Architecture of the U6 snRNP reveals specific recognition of 3'-end processed U6 snRNA. Nature communications 23 29717126
2009 LSM1 over-expression in Saccharomyces cerevisiae depletes U6 snRNA levels. Nucleic acids research 23 19596813
2018 Genome-wide association study identifies novel recessive genetic variants for high TGs in an Arab population. Journal of lipid research 22 30108155
2008 Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: possible role in autosomal dominant retinitis pigmentosa. Molecular vision 17 18334927
2017 The sole LSm complex in Cyanidioschyzon merolae associates with pre-mRNA splicing and mRNA degradation factors. RNA (New York, N.Y.) 14 28325844
2023 Identification of LSM family members as potential chemoresistance predictive and therapeutic biomarkers for gastric cancer. Frontiers in oncology 13 37007092
2022 The cytoplasmic LSm1-7 and nuclear LSm2-8 complexes exert opposite effects on Hepatitis B virus biosynthesis and interferon responses. Frontiers in immunology 9 36016928
2018 Defining essential elements and genetic interactions of the yeast Lsm2-8 ring and demonstration that essentiality of Lsm2-8 is bypassed via overexpression of U6 snRNA or the U6 snRNP subunit Prp24. RNA (New York, N.Y.) 8 29615482
2009 Analysis of Lsm1p and Lsm8p domains in the cellular localization of Lsm complexes in budding yeast. The FEBS journal 7 19490016
2024 The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop. Frontiers in toxicology 3 38694815
2025 Integrating multi-omics and machine learning methods reveals the metabolism of amino acids and derivatives-related signature in colorectal cancer. Frontiers in oncology 1 40206583
2025 Interconversion and mechanisms between Lsm-type and Sm-type heteroheptameric rings: implications for spliceosome evolution and RNA metabolism. Nucleic acids research 1 40433979
2026 A conserved Lsm8-exosome module maintains RNA splicing fidelity to control fungal stress adaptation and virulence. Stress biology 0 41663668
2020 A Nuclear RNA Degradation Pathway Helps Silence Polycomb/H3K27me3-Marked Loci in Caenorhabditis elegans. Cold Spring Harbor symposia on quantitative biology 0 32350050

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