id: O94822 gene_symbol: LTN1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 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. alternative_products: - name: '1' id: O94822-1 - name: '2' id: O94822-2 sequence_note: VSP_040138 - name: '3' id: O94822-3 sequence_note: VSP_044911 existing_annotations: - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: 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. action: ACCEPT reason: Cytosol is the correct site of action; supported by experimental IDA (PMID:25578875, PMID:28757607) and the UniProt subcellular location. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT reason: Directly supported experimentally; the RQC pathway degrades incompletely synthesized nascent chains via LTN1-mediated ubiquitination. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: mediates ubiquitination and extraction of incompletely synthesized nascent chains for proteasomal degradation - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: 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. action: ACCEPT reason: Core molecular function; corroborated by IDA (PMID:25578875), EC 2.3.2.27, and the C-terminal RING-CH domain. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase component of the ribosome quality control complex - term: id: GO:0072344 label: rescue of stalled cytosolic ribosome evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: By clearing the nascent chain from 60S-stalled complexes, LTN1 participates in resolving stalled ribosomes. Conserved RQC role. action: ACCEPT reason: Phylogenetically and experimentally supported; LTN1 is a defining factor of the stalled-ribosome rescue/RQC pathway. supported_by: - reference_id: PMID:25578875 supporting_text: the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin - term: id: GO:1990112 label: RQC complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: LTN1 is a constitutive component of the RQC complex (LTN1 + NEMF + TCF25) on the 60S subunit. action: ACCEPT reason: Directly demonstrated; LTN1 is one of the three defining RQC complex subunits. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit - term: id: GO:0043023 label: ribosomal large subunit binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: 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. action: ACCEPT reason: Structurally and biochemically demonstrated; LTN1 cofractionates with and binds 60S-nascent chain complexes. supported_by: - reference_id: PMID:25578875 supporting_text: Listerin's C-terminal RWD domain directly contacts the ribosome to position the adjacent ligase domain near the nascent polypeptide exit tunnel - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of the cytosol localization from the UniProt subcellular location, consistent with stronger experimental evidence. action: ACCEPT reason: Redundant with IDA cytosol annotations; correct compartment. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0008270 label: zinc ion binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: 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. action: KEEP_AS_NON_CORE reason: Accurate structural feature of the RING domain (residues 1715-1762) but subsidiary to the informative ubiquitin ligase activity; not a standalone core function. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: RING-type - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Electronic assignment of the core RING E3 ligase activity, consistent with the experimental IDA evidence and EC 2.3.2.27. action: ACCEPT reason: Correct core molecular function; redundant with IDA/IBA evidence. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: EC=2.3.2.27 - term: id: GO:1990112 label: RQC complex evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: InterPro-based electronic assignment to the RQC complex, consistent with the experimental IDA annotation. action: ACCEPT reason: Correct; LTN1 is a defining RQC complex subunit. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: Component of the ribosome quality control complex (RQC) - term: id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: InterPro-based electronic assignment of the RQC catabolic process, consistent with experimental evidence. action: ACCEPT reason: Correct defining biological process; redundant with IDA/IBA. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: mediates ubiquitination and extraction of incompletely synthesized nascent chains for proteasomal degradation - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21903422 qualifier: enables review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'O94822; Q92985: IRF7' - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Ortholog-based electronic transfer of ubiquitin-protein transferase activity, a parent/sibling of the more precise ubiquitin protein ligase activity that LTN1 enables. action: ACCEPT reason: Correct general molecular function; the more specific GO:0061630 captures the core RING E3 ligase activity. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: RING-type E3 ubiquitin transferase listerin - term: id: GO:0051865 label: protein autoubiquitination evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: LTN1 is autoubiquitinated, a common property of RING E3 ligases reflecting their catalytic activity on themselves. Peripheral to the substrate-directed function. action: KEEP_AS_NON_CORE reason: Supported by the UniProt PTM (autoubiquitinated) but a secondary property of the ligase, not its core nascent-chain-directed function. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: Autoubiquitinated - term: id: GO:0072344 label: rescue of stalled cytosolic ribosome evidence_type: TAS original_reference_id: Reactome:R-HSA-9948299 qualifier: involved_in review: summary: Reactome curation of LTN1 in stalled-ribosome rescue, consistent with experimental evidence and the IBA/IDA annotations. action: ACCEPT reason: Correct; redundant with experimentally supported RQC role. supported_by: - reference_id: PMID:25578875 supporting_text: the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: General protein ubiquitination process annotation derived from the UniPathway ubiquitination pathway; a parent of the specific RQC catabolic process. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific GO:1990116 (RQC ubiquitin-dependent catabolism) better captures LTN1's biological role. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-9948362 qualifier: enables review: summary: Reactome curation of the core RING E3 ligase activity of LTN1, consistent with experimental evidence. action: ACCEPT reason: Correct core molecular function. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase component of the ribosome quality control complex - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, consistent with LTN1's site of action. action: ACCEPT reason: IDA-supported cytosolic localization agrees with the documented cytoplasmic site of action. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0072344 label: rescue of stalled cytosolic ribosome evidence_type: NAS original_reference_id: PMID:35452614 qualifier: involved_in review: summary: Review-based (NAS, ComplexPortal) assertion of LTN1's role in stalled-ribosome rescue, drawn from the RQC review by Filbeck et al. action: ACCEPT reason: Consistent with the experimentally supported RQC role; the cited review summarizes RQC mechanisms from bacteria to humans. supported_by: - reference_id: PMID:35452614 supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans - term: id: GO:1990112 label: RQC complex evidence_type: NAS original_reference_id: PMID:35452614 qualifier: part_of review: summary: Review-based (NAS, ComplexPortal) assertion of LTN1 as an RQC complex component. action: ACCEPT reason: Consistent with experimentally demonstrated RQC complex membership. supported_by: - reference_id: PMID:35452614 supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans - term: id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:35452614 qualifier: involved_in review: summary: Review-based (NAS, ComplexPortal) assertion of LTN1's RQC ubiquitin-dependent catabolic role. action: ACCEPT reason: Consistent with the experimentally supported defining process. supported_by: - reference_id: PMID:35452614 supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans - term: id: GO:0022626 label: cytosolic ribosome evidence_type: IDA original_reference_id: PMID:25578875 qualifier: is_active_in review: summary: LTN1 acts on the cytosolic (60S) ribosome; the cryo-EM RQC complex study places Listerin directly on the 60S subunit. action: ACCEPT reason: Directly demonstrated; LTN1 functions while bound to the cytosolic ribosome. supported_by: - reference_id: PMID:25578875 supporting_text: the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin - term: id: GO:0072344 label: rescue of stalled cytosolic ribosome evidence_type: IDA original_reference_id: PMID:25578875 qualifier: involved_in review: summary: Direct experimental evidence that Listerin acts on stalled 60S-nascent chain complexes within the RQC pathway. action: ACCEPT reason: Core, experimentally supported RQC/rescue function. supported_by: - reference_id: PMID:25578875 supporting_text: its mammalian homolog Listerin was both necessary and sufficient for ubiquitination of stalled translation products - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:25578875 qualifier: enables review: 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. action: ACCEPT reason: Core molecular function with direct experimental (IDA) support and structural basis (C-terminal RING-CH domain). supported_by: - reference_id: PMID:25578875 supporting_text: the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:25578875 qualifier: located_in review: summary: Direct evidence for cytosolic localization of Listerin. action: ACCEPT reason: Correct compartment; LTN1 acts in the cytosol on ribosomes. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:1990112 label: RQC complex evidence_type: IDA original_reference_id: PMID:25578875 qualifier: part_of review: summary: The cryo-EM structure resolves Listerin as part of the RQC complex bound to the 60S-nascent chain, with NEMF bridging. action: ACCEPT reason: Directly demonstrated structurally; LTN1 is a defining RQC complex subunit. supported_by: - reference_id: PMID:25578875 supporting_text: ribosome-bound NEMF recruits and stabilizes Listerin's N-terminal domain - term: id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:25578875 qualifier: involved_in review: summary: Direct evidence that Listerin ubiquitinates 60S-stalled nascent chains, committing them to proteasomal degradation. action: ACCEPT reason: Core, experimentally supported defining biological process. supported_by: - reference_id: PMID:25578875 supporting_text: the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:28757607 qualifier: located_in review: 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. action: ACCEPT reason: Correct compartment, consistent with stronger LTN1-specific evidence; the source paper primarily concerns the 40S/Hel2 branch but the localization is accurate. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9948318 qualifier: located_in review: summary: Reactome curation of LTN1 cytosolic localization. action: ACCEPT reason: Correct compartment; redundant with experimental cytosol annotations. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9948362 qualifier: located_in review: summary: Reactome curation of LTN1 cytosolic localization. action: ACCEPT reason: Correct compartment; redundant with experimental cytosol annotations. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9948427 qualifier: located_in review: summary: Reactome curation of LTN1 cytosolic localization. action: ACCEPT reason: Correct compartment; redundant with experimental cytosol annotations. supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol' references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic Assertion of Orthology findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:21903422 title: Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput innate-immunity interactome; source of the IntAct protein binding partners (IRF7, STING1, TIRAP). Not relevant to LTN1's RQC ligase function. - id: PMID:25578875 title: Structure and assembly pathway of the ribosome quality control complex. findings: - statement: Listerin is the E3 ligase that poly-ubiquitinates 60S-housed nascent polypeptides during RQC, and its specificity for nascent chain-60S complexes depends on NEMF. reference_section_type: ABSTRACT - statement: NEMF recruits and stabilizes Listerin's N-terminal domain on the 60S while Listerin's C-terminal RWD domain contacts the ribosome to position the RING ligase domain near the nascent polypeptide exit tunnel. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Definitive structural/mechanistic study of the human RQC complex; establishes LTN1 as the RQC ligase and the NEMF dependence. - id: PMID:28757607 title: Ubiquitination of stalled ribosome triggers ribosome-associated quality control. findings: - statement: Establishes the upstream RQC trigger in which Hel2/RQT1 ubiquitinates the 40S protein uS10; provides the cytosolic RQC context in which LTN1 acts on the 60S branch. reference_section_type: ABSTRACT reference_review: relevance: LOW correctness: VERIFIED review_notes: Primarily about the 40S/Hel2(ZNF598-ortholog) branch; cited in LTN1 GOA only for cytosol localization. - id: PMID:35452614 title: Ribosome-associated quality-control mechanisms from bacteria to humans. findings: - statement: Review summarizing RQC, including LTN1/Listerin as the RQC complex E3 ligase that ubiquitinates stalled nascent chains for degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authoritative RQC review used by ComplexPortal for NAS annotations. - id: Reactome:R-HSA-9948299 title: 'Reactome: rescue of stalled ribosome (LTN1)' findings: [] - id: Reactome:R-HSA-9948318 title: 'Reactome: LTN1 cytosol localization' findings: [] - id: Reactome:R-HSA-9948362 title: 'Reactome: LTN1 ubiquitin ligase activity' findings: [] - id: Reactome:R-HSA-9948427 title: 'Reactome: LTN1 cytosol localization' findings: [] - id: file:human/LTN1/LTN1-uniprot.txt title: UniProt entry O94822 (LTN1_HUMAN), E3 ubiquitin-protein ligase listerin findings: - statement: E3 ubiquitin-protein ligase component of the RQC complex (LTN1, TCF25, NEMF) on the 60S subunit; recruited to stalled 60S by NEMF and ubiquitinates stalled nascent chains for proteasomal extraction/degradation via VCP/p97; RING-type ligase, EC 2.3.2.27; cytosolic. reference_section_type: OTHER core_functions: - description: RING-type E3 ubiquitin ligase that poly-ubiquitinates incompletely synthesized nascent polypeptides housed in the stalled 60S ribosomal subunit, marking them for VCP/p97 extraction and proteasomal degradation. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity locations: - id: GO:0022626 label: cytosolic ribosome supported_by: - reference_id: PMID:25578875 supporting_text: the 60S-housed nascent polypeptides are poly-ubiquitinated by Listerin - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase component of the ribosome quality control complex - description: Catalytic component of the ribosome quality control (RQC) complex that, recruited to 60S-nascent chain complexes by NEMF, mediates ribosome-associated ubiquitin-dependent degradation of stalled translation products and contributes to rescue of stalled ribosomes. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity in_complex: id: GO:1990112 label: RQC complex supported_by: - reference_id: file:human/LTN1/LTN1-uniprot.txt supporting_text: Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit - reference_id: PMID:25578875 supporting_text: ribosome-bound NEMF recruits and stabilizes Listerin's N-terminal domain directly_involved_in: - id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: 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? - question: Do the innate-immunity interactions (IRF7/STING1/TIRAP) reflect a genuine moonlighting role for LTN1 or are they incidental high-throughput captures? suggested_experiments: - description: 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. - description: CRISPR knockout of LTN1 in human cells followed by proteomics of stabilized, CAT-tailed aggregation-prone nascent chains to define the endogenous substrate repertoire.