LSG1

LSG1 is a conserved circularly permuted GTPase that catalyzes a late, cytoplasmic step of large (60S) ribosomal subunit maturation by driving release and nuclear recycling of the export adapter NMD3 (PMID:15660131). In yeast, lsg1 mutants fail to recycle Nmd3p from cytoplasmic 60S subunits, which indirectly blocks pre-60S nuclear export, a defect suppressed by NMD3 overexpression (PMID:15660131). Cryo-EM places Lsg1 together with Nmd3 near the peptidyl-transferase center of a defined late pre-60S intermediate that still lacks uL16, uL10, uL11, eL40 and eL41, providing the structural context for the maturation checkpoint (PMID:28112732). NMD3 release is coupled to loading of ribosomal protein Rpl10p (uL16) by the chaperone Sqt1p, which a dominant Walker A Lsg1p mutant traps in complex with Lsg1p and Nmd3p, and depends on a dynamic central loop of Rpl10p (PMID:15831484, PMID:17761675). Lsg1's intrinsic GTPase activity is stimulated by the Nmd3·60S particle, which acts as a GTP-stabilizing factor and links nucleotide turnover to substrate engagement (PMID:32916301). Separately, human LSG1 docks onto ER-membrane VAPs through a noncanonical FFAT-like motif; deletion of this motif abolishes ER localization without affecting NMD3 recycling or GTPase activity, establishing the ER-targeting role as functionally separable from ribosome assembly (PMID:39133101). Consistent with this, LSG1 inhibition in human cells induces senescence through perturbed ER homeostasis and upregulated cholesterol biosynthesis rather than translational insufficiency (PMID:31148378).

1. 2005 High

   Established the core function of LSG1: it is the cytoplasmic factor that recycles the 60S export adapter NMD3, resolving why its loss blocks pre-60S nuclear export.

   Evidence Genetic epistasis, NMD3-overexpression suppression and Nmd3-GFP shuttling assays in yeast lsg1 mutants

   PMID:15660131

   Open questions at the time

   • Did not show the structural basis of NMD3 release
   • GTP hydrolysis cycle not directly measured
2. 2005 Medium

   Connected NMD3 release to ribosomal protein loading by showing a GTPase-dead Lsg1p traps the Rpl10p chaperone Sqt1p and a defective Rpl10p, implying uL16 loading is part of the release mechanism.

   Evidence Co-IP with a dominant-negative Walker A LSG1 mutant plus genetic suppression in yeast

   PMID:15831484

   Open questions at the time

   • Order of uL16 loading versus NMD3 release not resolved
   • Relies on a trapping mutant rather than wild-type kinetics
3. 2005 Medium

   Extended the factor to humans, showing hLSG1 is essential and predominantly ER-localized, raising the question of an ER-associated role distinct from ribosome biogenesis.

   Evidence siRNA essentiality and subcellular imaging in human cells

   PMID:16209721

   Open questions at the time

   • Mechanism of ER targeting unknown
   • Functional meaning of ER localization not addressed
4. 2005 Low

   Placed LSG1 physically within a cytoplasmic pre-60S maturation complex by detecting association with TIF6 and the ABC protein ARB1.

   Evidence In vivo co-immunoprecipitation during ARB1 characterization in yeast

   PMID:16260602

   Open questions at the time

   • Single co-IP without reciprocal validation
   • Direct versus indirect association not distinguished
5. 2007 Medium

   Defined a specific structural element of Rpl10p required for the release reaction, showing the central loop has a dynamic rather than purely structural role in Lsg1-dependent NMD3 release.

   Evidence Mutational analysis of the Rpl10p central loop with Nmd3 release assays in yeast

   PMID:17761675

   Open questions at the time

   • Loop conformational dynamics not directly observed
   • Coupling to Lsg1 GTP hydrolysis not measured
6. 2013 Medium

   Confirmed the GTPase activity and conserved adapter-release function in a metazoan ortholog, linking LSG1 activity to sustained ribosome production and translation.

   Evidence Genetic loss-of-function and biochemical GTPase assay on Drosophila NS3

   PMID:23436180

   Open questions at the time

   • Substrate-stimulated kinetics not characterized
   • Ortholog inference for human mechanism
7. 2017 High

   Provided the structural snapshot of the LSG1 reaction, localizing Lsg1 and Nmd3 near the PTC on a late pre-60S intermediate lacking key r-proteins including uL16.

   Evidence Cryo-EM of Nmd3-purified yeast pre-60S particles

   PMID:28112732

   Open questions at the time

   • Lsg1 caught in a single state, not the catalytic cycle
   • Trigger for GTP hydrolysis not resolved structurally
8. 2018 Medium

   Revealed a non-ribosomal cytoplasmic role for the ortholog in retaining the cell-cycle repressor Prospero, mapping required GTP-binding and acidic domains.

   Evidence Genetic screen, domain structure-function and imaging of Drosophila NS3 in neuroblasts

   PMID:29679561

   Open questions at the time

   • Whether this reflects a moonlighting function or an indirect ribosome-biogenesis consequence is unresolved
   • Mammalian relevance untested
9. 2019 Medium

   Showed that human LSG1 loss causes senescence through ER stress and cholesterol-pathway upregulation rather than translational insufficiency, decoupling the human phenotype from ribosome depletion.

   Evidence LSG1 inhibition with transcriptomic, pathway and senescence assays in human cells

   PMID:31148378

   Open questions at the time

   • Direct molecular link between LSG1 and cholesterol genes not defined
   • Whether ER stress is cause or consequence unclear
10. 2020 Medium

    Quantified LSG1 enzymology, establishing intrinsic GTPase parameters and showing the Nmd3·60S particle stabilizes GTP binding, acting as a substrate-coupled activating factor.

    Evidence Fluorescence nucleotide-binding and steady-state kinetic GTPase assays with recombinant yeast Lsg1

    PMID:32916301

    Open questions at the time

    • GAP residues/mechanism of stimulation not mapped
    • Single in vitro study
11. 2024 High

    Defined the molecular basis of ER targeting and proved it is separable from catalysis: human LSG1 binds VAPs via a noncanonical FFAT-like motif whose deletion blocks ER localization but not NMD3 recycling or GTPase activity.

    Evidence Co-IP, FFAT-motif deletion mutagenesis, imaging and in vitro GTPase assay in human cells

    PMID:39133101

    Open questions at the time

    • Functional purpose of ER tethering not established
    • Link between ER localization and the senescence phenotype not demonstrated
12. 2026 Medium

    Genetically embedded LSG1 in a broader cytoplasmic assembly pathway, with bypass suppressor mutations reversing the eL24 loading defect of rei1Δ reh1Δ particles.

    Evidence Bypass suppressor screen with ribosomal protein composition analysis in yeast (preprint)

    PMID:41959095

    Open questions at the time

    • Preprint, not peer-reviewed
    • Mechanistic relationship between Lsg1 and eL24 loading not biochemically defined

• How LSG1's two activities — NMD3 recycling at the PTC and VAP-mediated ER tethering — are integrated, and how ER residence drives the cholesterol/senescence phenotype, remains unresolved.
• No mechanism linking ER localization to ribosome maturation
• Direct cause of cholesterol pathway upregulation unknown
• No structure of the human LSG1-VAP complex