LTN1 (Listerin, also RNF160/ZNF294) is a large (1766 aa) cytosolic RING-type E3 ubiquitin-protein ligase (EC 2.3.2.27) that is the catalytic core of the ribosome-associated quality control (RQC) complex. Its N-terminal HEAT/ARM-repeat solenoid wraps around the 60S large ribosomal subunit while its C-terminal RING-CH (RING-type zinc finger) domain catalyzes ubiquitin transfer. When an elongating 80S ribosome stalls and is split into subunits by the rescue factors PELO/HBS1L/ABCE1, the incomplete nascent polypeptide remains attached to a peptidyl-tRNA housed in the 60S subunit; LTN1 is recruited to these 60S-nascent chain complexes by NEMF, which senses the exposed P-site tRNA, and poly-ubiquitinates the trapped nascent chain. This commits aberrant translation products to extraction by the VCP/p97 AAA-ATPase and degradation by the proteasome, preventing accumulation of potentially toxic incomplete proteins. LTN1 thus functions in nascent-chain surveillance and rescue of stalled ribosomes; it is broadly expressed and acts in the cytosol in association with the 60S subunit.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: LTN1 acts in the cytosol in association with the 60S subunit and the RQC complex. The phylogenetic (IBA) cytosolic localization is consistent with direct experimental evidence and the documented cytoplasmic site of action. Reason: Cytosol is the correct site of action; supported by experimental IDA (PMID:25578875, PMID:28757607) and the UniProt subcellular location. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: LTN1 ubiquitinates 60S-stalled nascent chains to commit them to proteasomal degradation; this is its defining biological process and is well supported across the LTN1/Rkr1 family. Reason: Directly supported experimentally; the RQC pathway degrades incompletely synthesized nascent chains via LTN1-mediated ubiquitination. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt mediates ubiquitination and extraction of incompletely synthesized nascent chains for proteasomal degradation |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The core molecular function of Listerin is RING-type ubiquitin ligase activity, transferring ubiquitin to nascent-chain lysines. Conserved across the LTN1/Rkr1 family. Reason: Core molecular function; corroborated by IDA (PMID:25578875), EC 2.3.2.27, and the C-terminal RING-CH domain. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt E3 ubiquitin-protein ligase component of the ribosome quality control complex |
| GO:0072344 rescue of stalled cytosolic ribosome | IBA GO_REF:0000033 | ACCEPT | Summary: By clearing the nascent chain from 60S-stalled complexes, LTN1 participates in resolving stalled ribosomes. Conserved RQC role. Reason: Phylogenetically and experimentally supported; LTN1 is a defining factor of the stalled-ribosome rescue/RQC pathway. Supporting Evidence: PMID:25578875 the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin |
| GO:1990112 RQC complex | IBA GO_REF:0000033 | ACCEPT | Summary: LTN1 is a constitutive component of the RQC complex (LTN1 + NEMF + TCF25) on the 60S subunit. Reason: Directly demonstrated; LTN1 is one of the three defining RQC complex subunits. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit |
| GO:0043023 ribosomal large subunit binding | IBA GO_REF:0000033 | ACCEPT | Summary: LTN1's HEAT/ARM-repeat solenoid wraps the 60S large subunit, and its C-terminal RWD domain contacts the ribosome; binding the 60S subunit is integral to its function. Reason: Structurally and biochemically demonstrated; LTN1 cofractionates with and binds 60S-nascent chain complexes. Supporting Evidence: PMID:25578875 Listerin's C-terminal RWD domain directly contacts the ribosome to position the adjacent ligase domain near the nascent polypeptide exit tunnel |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of the cytosol localization from the UniProt subcellular location, consistent with stronger experimental evidence. Reason: Redundant with IDA cytosol annotations; correct compartment. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: The C-terminal RING-type zinc finger coordinates zinc as a structural requirement for the ligase fold. This is a structural attribute supporting, but not equal to, the ligase activity. Reason: Accurate structural feature of the RING domain (residues 1715-1762) but subsidiary to the informative ubiquitin ligase activity; not a standalone core function. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt RING-type |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the core RING E3 ligase activity, consistent with the experimental IDA evidence and EC 2.3.2.27. Reason: Correct core molecular function; redundant with IDA/IBA evidence. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt EC=2.3.2.27 |
| GO:1990112 RQC complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment to the RQC complex, consistent with the experimental IDA annotation. Reason: Correct; LTN1 is a defining RQC complex subunit. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt Component of the ribosome quality control complex (RQC) |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of the RQC catabolic process, consistent with experimental evidence. Reason: Correct defining biological process; redundant with IDA/IBA. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt mediates ubiquitination and extraction of incompletely synthesized nascent chains for proteasomal degradation |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | KEEP AS NON CORE | Summary: High-throughput innate-immunity interactome capturing LTN1 interactions with IRF7, STING1 and TIRAP. The bare protein binding term is uninformative and the partners are unrelated to LTN1's RQC ligase function. Reason: Records real IntAct interactions (IRF7/STING1/TIRAP) from an innate-immunity screen, but bare protein binding is uninformative and these partners do not reflect the core RQC ligase function; per guidelines not elevated to core. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt O94822; Q92985: IRF7 |
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic transfer of ubiquitin-protein transferase activity, a parent/sibling of the more precise ubiquitin protein ligase activity that LTN1 enables. Reason: Correct general molecular function; the more specific GO:0061630 captures the core RING E3 ligase activity. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt RING-type E3 ubiquitin transferase listerin |
| GO:0051865 protein autoubiquitination | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: LTN1 is autoubiquitinated, a common property of RING E3 ligases reflecting their catalytic activity on themselves. Peripheral to the substrate-directed function. Reason: Supported by the UniProt PTM (autoubiquitinated) but a secondary property of the ligase, not its core nascent-chain-directed function. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt Autoubiquitinated |
| GO:0072344 rescue of stalled cytosolic ribosome | TAS Reactome:R-HSA-9948299 | ACCEPT | Summary: Reactome curation of LTN1 in stalled-ribosome rescue, consistent with experimental evidence and the IBA/IDA annotations. Reason: Correct; redundant with experimentally supported RQC role. Supporting Evidence: PMID:25578875 the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: General protein ubiquitination process annotation derived from the UniPathway ubiquitination pathway; a parent of the specific RQC catabolic process. Reason: Correct but generic; the specific GO:1990116 (RQC ubiquitin-dependent catabolism) better captures LTN1's biological role. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0061630 ubiquitin protein ligase activity | TAS Reactome:R-HSA-9948362 | ACCEPT | Summary: Reactome curation of the core RING E3 ligase activity of LTN1, consistent with experimental evidence. Reason: Correct core molecular function. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt E3 ubiquitin-protein ligase component of the ribosome quality control complex |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, consistent with LTN1's site of action. Reason: IDA-supported cytosolic localization agrees with the documented cytoplasmic site of action. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0072344 rescue of stalled cytosolic ribosome | NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria... | ACCEPT | Summary: Review-based (NAS, ComplexPortal) assertion of LTN1's role in stalled-ribosome rescue, drawn from the RQC review by Filbeck et al. Reason: Consistent with the experimentally supported RQC role; the cited review summarizes RQC mechanisms from bacteria to humans. Supporting Evidence: PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria to humans |
| GO:1990112 RQC complex | NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria... | ACCEPT | Summary: Review-based (NAS, ComplexPortal) assertion of LTN1 as an RQC complex component. Reason: Consistent with experimentally demonstrated RQC complex membership. Supporting Evidence: PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria to humans |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria... | ACCEPT | Summary: Review-based (NAS, ComplexPortal) assertion of LTN1's RQC ubiquitin-dependent catabolic role. Reason: Consistent with the experimentally supported defining process. Supporting Evidence: PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria to humans |
| GO:0022626 cytosolic ribosome | IDA PMID:25578875 Structure and assembly pathway of the ribosome quality contr... | ACCEPT | Summary: LTN1 acts on the cytosolic (60S) ribosome; the cryo-EM RQC complex study places Listerin directly on the 60S subunit. Reason: Directly demonstrated; LTN1 functions while bound to the cytosolic ribosome. Supporting Evidence: PMID:25578875 the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:25578875 Structure and assembly pathway of the ribosome quality contr... | ACCEPT | Summary: Direct experimental evidence that Listerin acts on stalled 60S-nascent chain complexes within the RQC pathway. Reason: Core, experimentally supported RQC/rescue function. Supporting Evidence: PMID:25578875 its mammalian homolog Listerin was both necessary and sufficient for ubiquitination of stalled translation products |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:25578875 Structure and assembly pathway of the ribosome quality contr... | ACCEPT | Summary: Direct experimental demonstration that Listerin is the E3 ubiquitin ligase that poly-ubiquitinates 60S-housed nascent chains. This is LTN1's core molecular function. Reason: Core molecular function with direct experimental (IDA) support and structural basis (C-terminal RING-CH domain). Supporting Evidence: PMID:25578875 the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin |
| GO:0005829 cytosol | IDA PMID:25578875 Structure and assembly pathway of the ribosome quality contr... | ACCEPT | Summary: Direct evidence for cytosolic localization of Listerin. Reason: Correct compartment; LTN1 acts in the cytosol on ribosomes. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:1990112 RQC complex | IDA PMID:25578875 Structure and assembly pathway of the ribosome quality contr... | ACCEPT | Summary: The cryo-EM structure resolves Listerin as part of the RQC complex bound to the 60S-nascent chain, with NEMF bridging. Reason: Directly demonstrated structurally; LTN1 is a defining RQC complex subunit. Supporting Evidence: PMID:25578875 ribosome-bound NEMF recruits and stabilizes Listerin's N-terminal domain |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | IDA PMID:25578875 Structure and assembly pathway of the ribosome quality contr... | ACCEPT | Summary: Direct evidence that Listerin ubiquitinates 60S-stalled nascent chains, committing them to proteasomal degradation. Reason: Core, experimentally supported defining biological process. Supporting Evidence: PMID:25578875 the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin |
| GO:0005829 cytosol | IDA PMID:28757607 Ubiquitination of stalled ribosome triggers ribosome-associa... | ACCEPT | Summary: Cytosolic localization annotation derived from an RQC study (Matsuo et al. focused on Hel2/uS10 ubiquitination); consistent with LTN1's cytosolic site of action. Reason: Correct compartment, consistent with stronger LTN1-specific evidence; the source paper primarily concerns the 40S/Hel2 branch but the localization is accurate. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948318 | ACCEPT | Summary: Reactome curation of LTN1 cytosolic localization. Reason: Correct compartment; redundant with experimental cytosol annotations. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948362 | ACCEPT | Summary: Reactome curation of LTN1 cytosolic localization. Reason: Correct compartment; redundant with experimental cytosol annotations. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948427 | ACCEPT | Summary: Reactome curation of LTN1 cytosolic localization. Reason: Correct compartment; redundant with experimental cytosol annotations. Supporting Evidence: file:human/LTN1/LTN1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
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Download this section (compressed HTML)Q: How is LTN1 RING ligase activity spatially coordinated with NEMF-mediated CAT-tailing on the same 60S-nascent chain complex, and what determines the order of these events?
Q: Do the innate-immunity interactions (IRF7/STING1/TIRAP) reflect a genuine moonlighting role for LTN1 or are they incidental high-throughput captures?
Experiment: Reconstitute ubiquitination of defined 60S-nascent chain complexes with purified LTN1, NEMF and an E2 to map the lysine sites and ubiquitin chain topology Listerin builds on stalled nascent chains.
Experiment: CRISPR knockout of LTN1 in human cells followed by proteomics of stabilized, CAT-tailed aggregation-prone nascent chains to define the endogenous substrate repertoire.
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