DENR (Density-regulated protein, DRP) is a small cytoplasmic protein containing a C-terminal SUI1 (eIF1-like) domain. Together with its obligate partner MCTS1 it forms the MCTS1-DENR heterodimer, a non-canonical translation factor that is the functional equivalent of eIF2D (Ligatin) split into two polypeptides (MCTS1 corresponds to the N-terminal half, DENR to the C-terminal SUI1 half of Ligatin). The complex acts at the post-termination 40S ribosome to promote translation reinitiation, particularly after translation of short upstream ORFs (uORFs), enabling the small subunit to resume scanning and initiate at a downstream main ORF. Mechanistically the complex (i) promotes dissociation of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated splitting of post-termination complexes, and (ii) recruits aminoacylated initiator tRNA into the ribosomal P-site in an eIF2-independent manner when the start codon is already positioned in the P-site (as on certain HCV-like IRESs and reinitiation events). This activity governs the translation of a defined set of mRNAs (including JAK2), and MCTS1-DENR-dependent reinitiation is required for IFN-gamma immunity.
| 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 experimentally documented role of the MCTS1-DENR complex in assembling tRNA onto 40S/mRNA complexes for (re)initiation. Reason: The IBA is corroborated by direct experimental evidence that MCTS1/DENR promotes recruitment of initiator tRNA to 40S/mRNA complexes when the start codon is in the P-site. Supporting Evidence: file:human/DENR/DENR-uniprot.txt the recruitment in an EIF2-independent manner of aminoacylated initiator tRNA to P site of 40S ribosomes for a new round of translation |
| GO:0002188 translation reinitiation | IBA GO_REF:0000033 | ACCEPT | Summary: Translation reinitiation is the central, defining biological process of DENR, acting in the MCTS1-DENR complex after short uORFs to allow reinitiation at a downstream ORF. Reinitiation is selective for a subset of uORF-containing transcripts (not global uORF control), and DENR is functionally distinct from its single-chain homolog eIF2D. Reason: Strongly supported by both phylogenetic inference and direct experimental evidence (UniProt FUNCTION; ComplexPortal IDA), and is core to DENR function. Recent review/biochemical literature synthesized in the falcon deep research reinforces the uORF-selective reinitiation role of the DENR-MCTS1 complex. Supporting Evidence: file:human/DENR/DENR-uniprot.txt Translation regulator forming a complex with MCTS1 to promote translation reinitiation. file:human/DENR/DENR-deep-research-falcon.md DENR enables post-termination 40S subunits to resume scanning and initiate translation at downstream start codons, most critically at the main ORF of the mRNA |
| GO:0002183 cytoplasmic translational initiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Automated (ARBA) assignment of cytoplasmic translational initiation. DENR does participate in cytoplasmic (re)initiation, but its specific role is non-canonical reinitiation/recycling rather than canonical initiation. Reason: Broadly correct compartment and process, but more general than DENR's specific reinitiation/recycling role; retained as non-core. Supporting Evidence: file:human/DENR/DENR-uniprot.txt the recruitment in an EIF2-independent manner of aminoacylated initiator tRNA to P site of 40S ribosomes for a new round of translation |
| GO:0003743 translation initiation factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro/SUI1-domain-based assignment of translation initiation factor activity. DENR contributes the SUI1 module of the MCTS1-DENR complex that delivers tRNA to the 40S P-site, so this molecular function is appropriate. Reason: The eIF2D-like (re)initiation-factor activity is experimentally established for the MCTS1-DENR complex; DENR is an essential subunit. This is a core molecular function. Supporting Evidence: file:human/DENR/DENR-uniprot.txt the recruitment in an EIF2-independent manner of aminoacylated initiator tRNA to P site of 40S ribosomes for a new round of translation |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated cytoplasmic localization, consistent with the experimentally determined cytoplasmic site of action. Reason: Agrees with IDA cytoplasm evidence (PMID:16982740); DENR acts on cytoplasmic ribosomes. Supporting Evidence: file:human/DENR/DENR-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006413 translational initiation | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: General translational initiation, assigned from the SUI1 domain. DENR's specific role is non-canonical reinitiation and recycling rather than canonical cap-dependent initiation. Reason: Correct parent process but less informative than the specific reinitiation role; retained as non-core. Supporting Evidence: file:human/DENR/DENR-uniprot.txt Translation regulator forming a complex with MCTS1 to promote translation reinitiation. |
| GO:0005515 protein binding | IPI PMID:16169070 A human protein-protein interaction network: a resource for ... | KEEP AS NON CORE | Summary: IntAct interaction with MCTS1 (Q9ULC4), DENR's obligate functional partner. The bare protein binding term is uninformative, but the interaction itself is central to DENR function as part of the MCTS1-DENR heterodimer. Reason: Records a real and functionally pivotal MCTS1 interaction; per curation guidelines bare protein binding is not elevated to core, but the heterodimerization is captured in core_functions. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16169070 UniProtKB:Q9ULC4 |
| GO:0005515 protein binding | IPI PMID:16874301 A novel mitochondrial ubiquitin ligase plays a critical role... | KEEP AS NON CORE | Summary: IntAct interactions with UBC (P0CG48) and MARCHF5 (Q9NX47) from a high-throughput screen, unrelated to DENR's reinitiation function. Reason: Bare protein binding from high-throughput screens with partners not connected to the MCTS1-DENR reinitiation/recycling function; uninformative and non-core. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16874301 UniProtKB:Q9NX47 |
| GO:0005515 protein binding | IPI PMID:16936636 MARCH-V is a novel mitofusin 2- and Drp1-binding protein abl... | KEEP AS NON CORE | Summary: IntAct interactions with UBC (P0CG48) and MARCHF5 (Q9NX47); high-throughput, not connected to DENR's translation function. Reason: Bare protein binding from high-throughput screens with partners unrelated to reinitiation; uninformative and non-core. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16936636 UniProtKB:Q9NX47 |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | KEEP AS NON CORE | Summary: IntAct interaction with NELFB (Q8WX92) from a high-throughput screen; not related to DENR's reinitiation/recycling function. Reason: Bare protein binding from a high-throughput screen with a partner unrelated to DENR's core function; uninformative. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20195357 UniProtKB:Q8WX92 |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: IntAct interaction with MCTS1 (Q9ULC4), the obligate DENR partner. Reason: Records the functionally central MCTS1 interaction; bare protein binding is not elevated to core but the heterodimer is captured in core_functions. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:21516116 UniProtKB:Q9ULC4 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: IntAct interaction with MCTS1 (Q9ULC4), the obligate DENR partner. Reason: Records the functionally central MCTS1 interaction; bare protein binding is not elevated to core but the heterodimer is captured in core_functions. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:Q9ULC4 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex interactions including MCTS1 (Q9ULC4) and MAPT/tau (P10636). The MCTS1 interaction is functionally central; the tau interaction is a high-throughput observation. Reason: Captures the functionally central MCTS1 interaction (alongside a peripheral tau hit); bare protein binding is not elevated to core. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q9ULC4 |
| GO:0005515 protein binding | IPI PMID:34757590 Targeting Tau Mitigates Mitochondrial Fragmentation and Oxid... | KEEP AS NON CORE | Summary: IntAct interaction with MAPT/tau (P10636) from a high-throughput study; not connected to DENR's reinitiation function. Reason: Bare protein binding from a high-throughput screen with tau, unrelated to DENR's core function; uninformative. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:34757590 UniProtKB:P10636 |
| 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 MCTS1 (Q9ULC4), the obligate DENR partner. Reason: Records the functionally central MCTS1 interaction; bare protein binding is not elevated to core but is captured in core_functions. Supporting Evidence: file:human/DENR/DENR-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054 UniProtKB:Q9ULC4 |
| 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, demonstrated for JAK2 and other targets. Reason: Direct experimental support for the core reinitiation function of DENR within the MCTS1-DENR complex. Supporting Evidence: file:human/DENR/DENR-uniprot.txt Translation regulator forming a complex with MCTS1 to promote translation reinitiation. |
| GO:0070992 translation initiation complex | IPI PMID:29889857 DENR-MCTS1 heterodimerization and tRNA recruitment are requi... | ACCEPT | Summary: DENR is part of the MCTS1-DENR (re)initiation complex; heterodimerization with MCTS1 and tRNA recruitment are required for reinitiation. Reason: Supported by structural/biochemical demonstration that DENR-MCTS1 heterodimerize to form the functional reinitiation complex. Supporting Evidence: PMID:29889857 DENR-MCTS1 heterodimerization and tRNA recruitment are required for translation reinitiation |
| 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 MCTS1 (Q9ULC4); this is the foundational report that DENR/DRP is recruited by MCTS1 via the PUA/SUI1 interface. Reason: Records the functionally central MCTS1 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 DENR is active in the cytoplasm, where it associates with the cap complex/translation machinery via MCTS1. Reason: IDA-supported cytoplasmic site of action, consistent with DENR's role on cytoplasmic ribosomes. Supporting Evidence: file:human/DENR/DENR-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| 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 DENR's P-site tRNA delivery activity (viral IRES context); retained as 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, forming a preinitiation-type complex for reinitiation/recycling. Reason: Direct experimental support for DENR'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, i.e. the recycling/recovery step. Recent reviews reinforce that this tRNA-release/40S-recycling activity (a property of the DENR-MCTS1 complex) is a defining function and that penultimate-codon identity in the uORF modulates the efficiency of DENR-MCTS1-dependent recycling. Reason: Direct experimental support for DENR's role in 40S recycling (clearing deacylated tRNA/mRNA), a core part of its function, corroborated by recent review literature synthesized in the falcon deep research. Recycling is a property of the DENR-MCTS1 heterodimer, of which DENR is the essential SUI1-bearing subunit. 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 file:human/DENR/DENR-deep-research-falcon.md This tRNA release is essential for 40S ribosome dissociation from mRNA and recycling back into the translational pool |
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Download this section (compressed HTML)Q: What determines the subset of >150 mRNAs whose reinitiation depends on MCTS1-DENR, and do uORF features (length, Kozak context, terminator distance) predict dependence?
Q: Does phosphorylation of DENR (Ser-73 and other mitotic sites) regulate MCTS1-DENR complex assembly or reinitiation activity?
Q: To what extent can the MCTS1 paralog MCTS2 substitute for MCTS1 as a DENR partner in vivo, and does DENR-MCTS2 have distinct transcript selectivity from DENR-MCTS1?
Experiment: Ribosome profiling in DENR-knockout versus wild-type cells to map reinitiation-dependent mORFs genome-wide and define uORF determinants of MCTS1-DENR dependence.
Experiment: Reconstituted 40S recycling assays with purified DENR/MCTS1, ABCE1 and post-termination complexes to quantify the kinetics of deacylated tRNA/mRNA release contributed by DENR.
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