MCTS1 (Malignant T-cell-amplified sequence 1, MCT-1) is a cytoplasmic PUA-domain RNA-binding protein that, together with its obligate partner DENR, forms the MCTS1-DENR heterodimer, a non-canonical translation factor equivalent to eIF2D (Ligatin) split into two polypeptides (MCTS1 corresponds to the N-terminal half and DENR to the C-terminal SUI1 half). MCTS1 contributes the PUA domain that engages mRNA/the cap region and binds the 40S small ribosomal subunit, and recruits DENR. The complex acts at the post-termination 40S ribosome to promote translation reinitiation, particularly after short upstream ORFs (uORFs), and to recycle/recover post-termination 40S subunits by promoting release of deacylated tRNA and mRNA after ABCE1-mediated ribosome splitting; it also delivers initiator tRNA to the 40S P-site in an eIF2-independent manner when the start codon is positioned in the P-site (as on HCV-like IRESs). MCTS1-DENR-dependent reinitiation governs translation of a specific set of mRNAs (including JAK2) and is required for IFN-gamma immunity. MCTS1 was originally identified as an oncogene amplified in T-cell lymphoma.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001731 formation of translation preinitiation complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic transfer of preinitiation-complex formation, consistent with the MCTS1-DENR complex assembling tRNA onto 40S/mRNA complexes for (re)initiation. Reason: Corroborated by direct experimental evidence that MCT-1/DENR promotes recruitment of initiator tRNA to 40S/mRNA complexes. Supporting Evidence: PMID:20713520 promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes |
| GO:0002188 translation reinitiation | IEA GO_REF:0000117 | ACCEPT | Summary: Automated assignment of translation reinitiation, the central biological process of the MCTS1-DENR complex. Reason: Strongly supported by direct experimental and IMP/IDA evidence for the MCTS1-DENR complex; this is core to MCTS1 function. Supporting Evidence: PMID:29889857 DENR-MCTS1 heterodimerization and tRNA recruitment are required for translation reinitiation |
| GO:0003723 RNA binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro PUA-domain-based assignment of RNA binding. MCTS1 has a PUA domain and engages mRNA/cap region; RNA binding is a reasonable parent molecular function. Reason: Correct but generic; the specific informative activities are 40S binding, cap-complex/PUA-mediated mRNA engagement and reinitiation-factor activity. Supporting Evidence: PMID:16982740 MCT-1 contains the PUA domain, a recently described RNA-binding domain |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated cytoplasmic localization, consistent with experimental evidence. Reason: Agrees with EXP/IDA cytoplasm evidence; MCTS1 acts on cytoplasmic ribosomes. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005737 cytoplasm cellular_component ECO:0000269 EXP PMID:11709712 |
| GO:0005515 protein binding | IPI PMID:16169070 A human protein-protein interaction network: a resource for ... | KEEP AS NON CORE | Summary: IntAct interaction with DENR (O43583), MCTS1's obligate functional partner. Reason: Records the functionally central DENR interaction; bare protein binding is not elevated to core but the heterodimer is captured in core_functions. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16169070 UniProtKB:O43583 |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: IntAct interaction with DENR (O43583), the obligate MCTS1 partner. Reason: Records the functionally central DENR interaction; bare protein binding is not elevated to core but the heterodimer is captured in core_functions. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:21516116 UniProtKB:O43583 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: IntAct interaction with DENR (O43583), the obligate MCTS1 partner. Reason: Records the functionally central DENR interaction; bare protein binding is not elevated to core but the heterodimer is captured in core_functions. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:O43583 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex interaction with DENR (O43583), the obligate MCTS1 partner. Reason: Records the functionally central DENR interaction; bare protein binding is not elevated to core but the heterodimer is captured in core_functions. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:O43583 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Cell-maps interactome interaction with DENR (O43583), the obligate MCTS1 partner. Reason: Records the functionally central DENR interaction; bare protein binding is not elevated to core but the heterodimer is captured in core_functions. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054 UniProtKB:O43583 |
| GO:0002188 translation reinitiation | IDA PMID:37875108 Human MCTS1-dependent translation of JAK2 is essential for I... | ACCEPT | Summary: Direct evidence (ComplexPortal/IDA) that the MCTS1-DENR complex mediates translation reinitiation, shown for JAK2 and other targets. Reason: Direct experimental support for the core reinitiation function of MCTS1. Supporting Evidence: PMID:37875108 Human MCTS1-dependent translation of JAK2 is essential for IFN-Ξ³ immunity to mycobacteria. |
| GO:0070992 translation initiation complex | IPI PMID:29889857 DENR-MCTS1 heterodimerization and tRNA recruitment are requi... | ACCEPT | Summary: MCTS1 is part of the MCTS1-DENR (re)initiation complex; heterodimerization with DENR and tRNA recruitment are required for reinitiation. Reason: Supported by structural/biochemical demonstration that MCTS1-DENR heterodimerize to form the functional reinitiation complex. Supporting Evidence: PMID:29889857 DENR-MCTS1 heterodimerization and tRNA recruitment are required for translation reinitiation |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) cytosolic localization, consistent with the cytoplasmic site of action. Reason: IDA-supported cytosolic localization agrees with MCTS1's role on cytoplasmic ribosomes. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005829 cytosol cellular_component ECO:0000314 IDA GO_REF:0000052 |
| GO:0005737 cytoplasm | EXP PMID:11709712 Expression and stabilization of the MCT-1 protein by DNA dam... | ACCEPT | Summary: Experimental cytoplasmic localization from the original MCT-1 oncogene characterization. Reason: Experimentally supported cytoplasmic localization consistent with MCTS1's site of action. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005737 cytoplasm cellular_component ECO:0000269 EXP PMID:11709712 |
| GO:0003743 translation initiation factor activity | IDA PMID:20713520 Activities of Ligatin and MCT-1/DENR in eukaryotic translati... | ACCEPT | Summary: Direct evidence that MCT-1/DENR functions as a non-canonical (eIF2D-like) factor that delivers initiator tRNA to the 40S P-site; this is a core molecular function. Reason: Experimentally established (re)initiation-factor activity of the MCTS1-DENR complex; MCTS1 is an essential subunit. Supporting Evidence: PMID:20713520 promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes |
| GO:0000339 RNA cap binding | IDA PMID:16982740 MCT-1 protein interacts with the cap complex and modulates m... | KEEP AS NON CORE | Summary: MCT-1 interacts with the cap complex through its PUA domain. This was interpreted as cap-complex association; whether MCTS1 directly binds the m7G cap or associates via the cap-binding complex is less certain, but the PUA-mediated engagement at the cap is documented. Reason: Supported by direct evidence of cap-complex interaction via the PUA domain, but the primary informative function is reinitiation/40S recycling; retained as non-core. Supporting Evidence: PMID:16982740 MCT-1 protein interacts with the cap complex through its PUA domain |
| GO:0005515 protein binding | IPI PMID:16982740 MCT-1 protein interacts with the cap complex and modulates m... | KEEP AS NON CORE | Summary: UniProt-curated interaction with DENR (O43583); the foundational report that MCT-1 recruits DENR/DRP via the PUA/SUI1 interface. Reason: Records the functionally central DENR interaction; bare protein binding is not elevated to core but the heterodimer is captured in core_functions. Supporting Evidence: PMID:16982740 recruits the density-regulated protein (DENR/DRP), containing the SUI1 translation initiation domain |
| GO:0005737 cytoplasm | IDA PMID:16982740 MCT-1 protein interacts with the cap complex and modulates m... | ACCEPT | Summary: Direct evidence that MCTS1 is active in the cytoplasm where it associates with the cap complex and 40S ribosomes. Reason: IDA-supported cytoplasmic site of action. Supporting Evidence: file:human/MCTS1/MCTS1-goa.tsv GO:0005737 cytoplasm cellular_component ECO:0000314 IDA PMID:16982740 |
| GO:0043024 ribosomal small subunit binding | IDA PMID:20713520 Activities of Ligatin and MCT-1/DENR in eukaryotic translati... | ACCEPT | Summary: MCT-1/DENR binds 40S small ribosomal subunits to deliver tRNA and to promote recycling; direct binding to the 40S subunit is a core molecular function. Reason: Direct experimental evidence of MCTS1-DENR action on 40S subunits; binding the small subunit underlies its reinitiation/recycling activities. Supporting Evidence: PMID:20713520 promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes |
| GO:0002188 translation reinitiation | IMP PMID:37875108 Human MCTS1-dependent translation of JAK2 is essential for I... | ACCEPT | Summary: Loss-of-function (patient) evidence that MCTS1 is required for translation reinitiation of specific mRNAs (e.g. JAK2). The JAK2 5'UTR carries three uORFs (two ultra-short start-stop uORFs); without MCTS1, post-uORF 40S ribosomes stall because deacylated tRNA is not removed, blocking reinitiation on the main JAK2 ORF. Reason: IMP evidence directly supports the core reinitiation function of MCTS1, with the JAK2 5'UTR uORF architecture providing the mechanistic basis for its dependence on MCTS1-DENR reinitiation. Supporting Evidence: PMID:37875108 Human MCTS1-dependent translation of JAK2 is essential for IFN-Ξ³ immunity to mycobacteria. PMID:37875108 We identified three uORFs within the JAK2 PMID:37875108 In the absence of MCTS1 or DENR, 40S ribosomes stall on the uORF stop codon, because the deacylated tRNA cannot be removed |
| GO:0032790 ribosome disassembly | IMP PMID:37875108 Human MCTS1-dependent translation of JAK2 is essential for I... | ACCEPT | Summary: Loss-of-function evidence linking MCTS1 to the 40S recycling/disassembly step that underpins reinitiation. The Bohlen 2023 full text directly assays MCTS1KO and patient cells, showing accumulation of stalled post-termination 40S subunits and 80S queueing when MCTS1 is absent, establishing impaired ribosome recycling as an MCTS1-specific defect. Reason: Consistent with the established role of MCTS1-DENR in clearing post-termination 40S subunits; supported by both IMP (MCTS1KO/patient-cell recycling defects) and the biochemical recycling assays. Supporting Evidence: PMID:20713520 Ligatin and MCT-1/DENR can promote release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated dissociation of post-termination ribosomes PMID:37875108 the DENR-MCTS1 complex removes the tRNA from the 40S ribosome on the stop codon, as a part of ribosome recycling PMID:37875108 MCTS1KO HeLa cells, thus, have impaired ribosome recycling file:human/MCTS1/MCTS1-deep-research-falcon.md loss of MCTS1 causes stalled post-termination 40S ribosomes at stop codons and 80S ribosome queueing upstream, demonstrating a role in ribosome recycling in addition to re-initiation |
| GO:0075522 IRES-dependent viral translational initiation | IDA PMID:20713520 Activities of Ligatin and MCT-1/DENR in eukaryotic translati... | KEEP AS NON CORE | Summary: MCT-1/DENR promotes eIF2-independent recruitment of initiator tRNA on HCV-like IRESs and SV 26S mRNA, where the start codon is placed directly in the P-site. Reason: A genuine but specialized application of MCTS1-DENR's P-site tRNA delivery activity (viral IRES context); non-core relative to cellular reinitiation. Supporting Evidence: PMID:20713520 promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes, if attachment of 40S subunits to the mRNA places the initiation codon directly in the P site, as on HCV-like IRESs |
| GO:0001731 formation of translation preinitiation complex | IDA PMID:20713520 Activities of Ligatin and MCT-1/DENR in eukaryotic translati... | ACCEPT | Summary: Direct evidence that MCT-1/DENR assembles initiator tRNA onto 40S/mRNA complexes for reinitiation/recycling. Reason: Direct experimental support for MCTS1's role in assembling the tRNA-loaded 40S complex. Supporting Evidence: PMID:20713520 promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes |
| GO:0032790 ribosome disassembly | IDA PMID:20713520 Activities of Ligatin and MCT-1/DENR in eukaryotic translati... | ACCEPT | Summary: MCT-1/DENR promotes release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated splitting of post-termination ribosomes. Reason: Direct experimental support for MCTS1's role in 40S recycling/recovery. Supporting Evidence: PMID:20713520 Ligatin and MCT-1/DENR can promote release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated dissociation of post-termination ribosomes |
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Download this section (compressed HTML)Q: Does MCTS1 directly bind the m7G cap, or is its association with the cap complex indirect (via eIF4 components), and how does the PUA domain contribute?
Q: Which features of target mRNAs (uORF architecture, 5' UTR structure) determine MCTS1-DENR dependence, and how does this relate to MCTS1's oncogenic activity?
Experiment: Cross-linking/CLIP of MCTS1 to define its direct RNA-binding sites genome-wide and test whether it contacts the cap-proximal region directly.
Experiment: Reconstituted 40S P-site tRNA delivery and recycling assays with purified MCTS1, DENR and ABCE1 to dissect MCTS1's specific contribution to each step.
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