Affinage

LSM8

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

Round 2 corrected
Length
96 aa
Mass
10.4 kDa
Annotated
2026-04-28
54 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LSm8 is the defining subunit of the nuclear heteroheptameric Lsm2–8 ring that binds the 3′-terminal oligo(U) tract of U6 snRNA to stabilize, chaperone, and deliver U6 into spliceosomes, constituting the sole essential function of Lsm8 in yeast (PMID:9857199, PMID:11333229, PMID:29615482). The Lsm2–8 ring assembles in the order Lsm3-2-8-4-7-5-6, with Lsm8 providing one of four uridine-recognition contacts through a conserved asparagine residue, and is positioned adjacent to the Prp24 chaperone active site within the U6 snRNP to facilitate spliceosome assembly (PMID:24240276, PMID:29717126). Beyond splicing, the Lsm2–8 complex participates in nuclear RNA surveillance—cooperating with XRN-2 and the exosome to degrade transcripts from H3K27me3-marked heterochromatic loci—and its nuclear accumulation is directed in part by the Lsm8 N-terminal domain, while its protein stability depends on Hsp90 and prefoldin cochaperones (PMID:32350050, PMID:19490016, PMID:32396196).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1998 High

    Identification of Lsm8 as a U6 snRNP subunit established that a dedicated Sm-like protein is required for mature U6 snRNP accumulation and revealed functional redundancy with the La protein Lhp1p in nascent U6 RNA stabilization.

    Evidence Genetic mutant analysis of lsm8-1 in S. cerevisiae combined with Northern blotting for U6 snRNA

    PMID:9857199

    Open questions at the time
    • No physical reconstitution of the Lsm ring
    • Mechanism of La/Lsm redundancy unresolved
  2. 1999 High

    Biochemical isolation of the Lsm2–8 heteromer from human tri-snRNPs and its selective binding to the U6 3′ oligo(U) tract demonstrated that the ring is a conserved RNA-recognition module that promotes U4/U6 duplex formation.

    Evidence Protein purification from human tri-snRNPs, electron microscopy, in vitro U4/U6 duplex formation assays, and co-immunoprecipitation of yeast and human Lsm proteins with U6 snRNA

    PMID:10369684 PMID:10523320

    Open questions at the time
    • Atomic-resolution structure unavailable
    • Individual subunit contributions to RNA binding unknown
  3. 2001 High

    Genetic epistasis showed that overexpression of U6 snRNA renders LSM8 dispensable, establishing that the sole essential function of Lsm8 is to support U6 snRNA biogenesis.

    Evidence Suppressor analysis and U6 gene overexpression in S. cerevisiae

    PMID:11333229

    Open questions at the time
    • Non-essential roles (e.g. RNA surveillance) not yet explored
    • No direct biochemical measurement of ring assembly kinetics
  4. 2009 Medium

    Domain swap experiments revealed that the Lsm8 N-terminus contributes to nuclear accumulation of the Lsm2–8 complex, and competition between Lsm1 and Lsm8 for shared Lsm2–7 subunits regulates U6 snRNA stability.

    Evidence Fluorescence microscopy of chimeric Lsm1/Lsm8 proteins and LSM1 overexpression with U6 Northern blots in yeast

    PMID:19490016 PMID:19596813

    Open questions at the time
    • Structural basis of nuclear targeting not defined
    • Quantitative competition dynamics between Lsm1 and Lsm8 not measured
  5. 2013 High

    Crystal structures of the Lsm2–8 ring at 2.8 Å revealed the subunit order (Lsm3-2-8-4-7-5-6) and a modular uridine-recognition mechanism in which Lsm8 uses a conserved asparagine to recognize one of four 3′-terminal uridines of U6 snRNA.

    Evidence X-ray crystallography of Lsm2–8 ± U6 3′ RNA fragment with biochemical binding validation

    PMID:24240276

    Open questions at the time
    • Full-length U6 snRNP structure not yet available
    • Dynamics of ring opening during RNA loading unknown
  6. 2018 High

    Cryo-EM of the yeast U6 snRNP showed the Lsm2–8 ring positioned adjacent to the Prp24 chaperone active site, explaining how processed U6 snRNA is selectively recruited for spliceosome assembly; structure-guided mutagenesis confirmed that supporting U6 is the only essential ring function.

    Evidence Cryo-EM of S. cerevisiae U6 snRNP and comprehensive alanine-scanning mutagenesis with lethality rescue assays

    PMID:29615482 PMID:29717126

    Open questions at the time
    • Transition state of U4/U6 duplex formation with Prp24 not captured
    • Human U6 snRNP structure not yet determined at equivalent resolution
  7. 2020 Medium

    The Lsm2–8 complex was shown to participate in nuclear RNA surveillance beyond splicing: in C. elegans it cooperates with XRN-2 to degrade transcripts from H3K27me3-marked loci, reinforcing heterochromatic silencing; in Arabidopsis, Lsm8 protein stability depends on Hsp90 and prefoldin cochaperones.

    Evidence Genetic epistasis and mRNA stability assays with ChIP in C. elegans; co-immunoprecipitation and Hsp90 inhibitor treatment with splicing analysis in Arabidopsis

    PMID:32350050 PMID:32396196

    Open questions at the time
    • RNA surveillance function not yet demonstrated in mammalian cells
    • Direct physical interaction between Lsm2-8 and XRN-2 not shown
    • Whether Hsp90 dependence is conserved in animals unknown
  8. 2025 Medium

    Ring interconversion experiments revealed that Lsm8/Lsm4 form a discrete subcomplex (SC3) whose interface strength with the Lsm2/3 subcomplex dictates whether the ring behaves as an Lsm-type or Sm-type complex, defining the structural basis of functional divergence.

    Evidence Mutagenesis-driven ring type conversion with structural and biochemical characterization

    PMID:40433979

    Open questions at the time
    • In vivo functional consequences of ring-type switching not tested
    • Physiological regulation of subcomplex interfaces unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how Lsm2–8 RNA surveillance functions integrate with the exosome in mammalian nuclei, the structural dynamics of U6 snRNA loading/unloading from the ring, and whether Lsm8 has non-spliceosomal roles in human cells.
  • No mammalian genetic loss-of-function study for RNA surveillance
  • No time-resolved structural data for ring–RNA dynamics
  • Potential role in m6A-dependent viral RNA regulation awaits independent confirmation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 2
Pathway
R-HSA-8953854 Metabolism of RNA 6
Partners
LSM2LSM3LSM4LSM5LSM6LSM7PRP24
Complex memberships
Lsm2-8 ringU4/U6.U5 tri-snRNPU6 snRNP

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Lsm8p was identified as a novel component of the yeast U6 snRNP and a member of the Sm-like protein family. The lsm8-1 mutation causes drastically reduced levels of mature U6 snRNP, implicating Lsm8p as a key component in the early steps of U6 snRNP assembly. The La protein Lhp1p stabilizes nascent U6 RNA in lsm8-1 cells, revealing a redundant chaperone role. Genetic mutant analysis, yeast growth assays, Northern blotting for U6 snRNA levels, molecular characterization of Sm motif The EMBO journal High 9857199
2001 Functional interactions within the Lsm2-8 complex were defined: LSM2 and LSM4 act as allele-specific suppressors of lsm8 mutations, and overexpression of LSM2 increases Lsm8p levels and U6 snRNP assembly. Overexpression of U6 snRNA genes renders LSM8 dispensable, indicating that the only essential function of LSM8 is in U6 RNA biogenesis or function. Deletions of LSM5, LSM6, or LSM7 also require Lhp1p, consistent with Lhp1p acting redundantly with the entire Lsm2-8 complex. Genetic suppressor analysis, gene overexpression, Northern blotting, immunoprecipitation of U6 snRNPs Genetics High 11333229
1999 Human LSm proteins (including LSm8) purified from [U4/U6.U5] tri-snRNPs form a stable doughnut-shaped heteromeric complex that specifically binds to the 3'-terminal U-tract of U6 snRNA. The LSm heteromer facilitates formation of U4/U6 RNA duplexes in vitro, suggesting a role in U4/U6 snRNP formation. Protein purification, electron microscopy, RNA-binding assays, in vitro U4/U6 duplex formation assay, co-immunoprecipitation The EMBO journal High 10523320
1999 Seven yeast Sm-like proteins, including Lsm8p, associate specifically with nuclear U6 snRNA and pre-RNase P RNA, forming a complex distinct from the cytoplasmic Lsm1-7 complex. Human homologs of Sm-like proteins including Lsm8 were shown to associate with U6 snRNA-containing complexes, demonstrating evolutionary conservation of this nuclear complex. Immunoprecipitation, database searches, cDNA cloning, co-immunoprecipitation of human Lsm proteins with U6 snRNA The EMBO journal High 10369684
2004 An Lsm2-Lsm7 sub-complex (lacking Lsm8) associates with the box H/ACA snoRNA snR5 in yeast. In vitro reconstitution experiments showed that the 3' end of snR5 is critical for Lsm protein recognition. Lsm proteins were detected in nucleoli by localization experiments, indicating a nucleolar pool of Lsm proteins distinct from the nuclear Lsm2-8 and cytoplasmic Lsm1-7 complexes. In vitro reconstitution of Lsm-snR5 binding, glycerol gradient sedimentation, sequential immunoprecipitation, subcellular localization Molecular biology of the cell Medium 15075370
2009 Domain analysis of Lsm1p and Lsm8p in budding yeast revealed that no single domain is essential or sufficient for cellular localization of the complexes. The Lsm8p N-terminus contributes to nuclear accumulation of the Lsm2-8p complex, while Lsm1p N-terminus may act as part of a nuclear exclusion signal for the cytoplasmic Lsm1-7p complex. C-terminal regions play a secondary role in localization. Mutant/hybrid protein analysis, fluorescence microscopy-based localization, yeast viability assays The FEBS journal Medium 19490016
2009 Overexpression of LSM1 in yeast depletes U6 snRNA levels by sequestering Lsm2-7 proteins away from Lsm8, thereby disrupting assembly of the Lsm2-8 complex that binds and stabilizes U6 snRNA. This demonstrates that Lsm8 is required for formation of the Lsm2-8·U6 snRNP and that competition between Lsm1 and Lsm8 for the shared Lsm2-7 subunits regulates U6 snRNA stability. LSM1 overexpression, Northern blotting for U6 snRNA, genetic hypersensitivity assays, pre-mRNA splicing assays Nucleic acids research Medium 19596813
2013 Crystal structures of the heptameric Lsm2-8 complex, alone and bound to the 3' fragment of U6 snRNA, were determined at 2.8 Å resolution. The ring order is Lsm3-2-8-4-7-5-6. Lsm8 is one of four subunits (Lsm3, Lsm2, Lsm8, Lsm4) that modularly recognize the four 3'-terminal uridine nucleotides of U6 snRNA, with uracil base specificity conferred by a conserved asparagine residue in each subunit. Biochemical analyses validated the structural contacts. X-ray crystallography at 2.8 Å, biochemical binding assays Nature High 24240276
2018 The cryo-EM structure of the yeast U6 snRNP revealed protein-protein contacts that position the Lsm2-8 ring in close proximity to the chaperone active site of Prp24. The structure shows that the Lsm2-8 ring specifically recognizes 3'-end post-transcriptionally processed U6 snRNA, elucidating the mechanism by which U6 snRNPs selectively recruit processed U6 snRNA into spliceosomes. The C-terminal region of Lsm8 shows unanticipated homology to the cytoplasmic Lsm1. Cryo-EM structure determination of the U6 snRNP from S. cerevisiae Nature communications High 29717126
2018 Structure-guided mutational analysis of the yeast Lsm2-8 ring demonstrated that lethal deletion of lsm8Δ (and other Lsm subunit deletions) is rescued by overexpression of U6 snRNA or by overexpression of the U6 snRNP protein Prp24, establishing that supporting U6 snRNA is the only essential function of the yeast Lsm2-8 proteins. Genetic redundancies buffer Lsm2-8 ring function. Alanine scanning mutagenesis, lethality rescue by U6 snRNA overexpression and Prp24 overexpression, pairwise synthetic lethality analysis RNA (New York, N.Y.) High 29615482
2020 In C. elegans, the LSM2-8 complex (including LSM-8) contributes to repression of heterochromatic genes bearing the Polycomb mark H3K27me3 by promoting RNA degradation cooperatively with the 5'-3' exoribonuclease XRN-2. Disruption of lsm-8 leads to selective mRNA stabilization of H3K27me3-marked loci and a localized drop in H3K27me3 levels, revealing a role for LSM2-8 in nuclear RNA surveillance that reinforces facultative heterochromatin silencing. Genetic screen, mRNA stability assays, chromatin immunoprecipitation (H3K27me3), epistasis with XRN-2 Cold Spring Harbor symposia on quantitative biology Medium 32350050
2022 siRNA-mediated knockdown of LSm8 in HBV replication/infection models reduced viral RNA levels in an m6A-dependent manner: LSm8 depletion reduced N6-adenosine methylation (m6A) of the epsilon stem-loop at the 5' end of preC/pgRNA, as demonstrated by methylated RNA immunoprecipitation (MeRIP). IFN-α treatment decreased LSm8 protein levels in G2/M phase, suggesting the nuclear LSm2-8 complex is pro-viral for HBV, in contrast to the antiviral cytoplasmic LSm1-7 complex. siRNA knockdown, MeRIP assay, proteomic analysis, IFN-α treatment, viral RNA quantification Frontiers in immunology Medium 36016928
2020 In Arabidopsis, prefoldins (PFDs) interact with and are required to maintain adequate levels of the LSM2-8 complex. LSM8 protein levels are reduced in pfd mutants and in response to the Hsp90 inhibitor geldanamycin. Biochemical evidence shows that LSM8 is a client of Hsp90 and that PFD4 mediates the interaction between LSM8 and Hsp90. Loss of PFD function leads to reduced U6 snRNA levels and altered pre-mRNA splicing. Co-immunoprecipitation, Hsp90 inhibitor treatment, splicing analysis, genetic mutant analysis in Arabidopsis Nucleic acids research Medium 32396196
2025 Mechanistic study of Sm and Lsm2-8 ring interconversion revealed that in the Lsm2-8 ring, subcomplex organization is Lsm2/3 (SC1), Lsm6/5/7 (SC2), and Lsm8/4 (SC3). By strengthening SC1-SC3 interactions, the Sm ring could be converted to an Lsm-type ring, while weakening SC1-SC3 interaction plus mutations in RNA-binding regions of SC1 and SC2 converted Lsm2-8 into a Sm-type ring, revealing mechanistic basis for functional divergence of the two ring types. Mutagenesis-driven ring interconversion, structural and biochemical characterization Nucleic acids research Medium 40433979

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2003 Splicing double: insights from the second spliceosome. Nature reviews. Molecular cell biology 329 14685174
2012 Dynamic protein-protein interaction wiring of the human spliceosome. Molecular cell 318 22365833
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
1999 A doughnut-shaped heteromer of human Sm-like proteins binds to the 3'-end of U6 snRNA, thereby facilitating U4/U6 duplex formation in vitro. The EMBO journal 260 10523320
1999 Sm and Sm-like proteins assemble in two related complexes of deep evolutionary origin. The EMBO journal 220 10369684
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2017 Cryo-EM Structure of a Pre-catalytic Human Spliceosome Primed for Activation. Cell 199 28781166
2003 The DNA sequence of human chromosome 7. Nature 188 12853948
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
2016 Molecular architecture of the human U4/U6.U5 tri-snRNP. Science (New York, N.Y.) 167 26912367
1999 Functional interaction of a novel 15.5kD [U4/U6.U5] tri-snRNP protein with the 5' stem-loop of U4 snRNA. The EMBO journal 167 10545122
2003 Human chromosome 7: DNA sequence and biology. Science (New York, N.Y.) 154 12690205
2007 An emerin "proteome": purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signaling, mechanosensing, and nuclear architecture. Biochemistry 153 17620012
2011 3' processing of eukaryotic precursor tRNAs. Wiley interdisciplinary reviews. RNA 115 21572561
2013 Crystal structures of the Lsm complex bound to the 3' end sequence of U6 small nuclear RNA. Nature 83 24240276
2013 Arabidopsis thaliana LSM proteins function in mRNA splicing and degradation. Nucleic acids research 71 23620288
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 43 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 38 24828406
2004 An Lsm2-Lsm7 complex in Saccharomyces cerevisiae associates with the small nucleolar RNA snR5. Molecular biology of the cell 37 15075370
2009 LSM1 over-expression in Saccharomyces cerevisiae depletes U6 snRNA levels. Nucleic acids research 23 19596813
2018 Architecture of the U6 snRNP reveals specific recognition of 3'-end processed U6 snRNA. Nature communications 22 29717126
2018 Genome-wide association study identifies novel recessive genetic variants for high TGs in an Arab population. Journal of lipid research 22 30108155
2020 Prefoldins contribute to maintaining the levels of the spliceosome LSM2-8 complex through Hsp90 in Arabidopsis. Nucleic acids research 19 32396196
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 8 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
2026 A conserved Lsm8-exosome module maintains RNA splicing fidelity to control fungal stress adaptation and virulence. Stress biology 0 41663668
2025 Interconversion and mechanisms between Lsm-type and Sm-type heteroheptameric rings: implications for spliceosome evolution and RNA metabolism. Nucleic acids research 0 40433979
2020 A Nuclear RNA Degradation Pathway Helps Silence Polycomb/H3K27me3-Marked Loci in Caenorhabditis elegans. Cold Spring Harbor symposia on quantitative biology 0 32350050