COPS2 (COP9 signalosome complex subunit 2, also known as TRIP15/Alien) is a core PCI-domain scaffold subunit of the COP9 signalosome (CSN), an eight-subunit protein complex essential for regulating the ubiquitin-proteasome pathway. COPS2 is a non-catalytic structural component that organizes the CSN complex and engages cullin-RING E3 ligases (CRLs) to enable CSN5-mediated deneddylation of cullins, thereby controlling CRL ubiquitin ligase activity and downstream proteostasis. COPS2 also functions independently as a nuclear receptor corepressor (Alien/TRIP15), interacting with thyroid hormone receptor, DAX-1, and other nuclear receptors to repress transcription. The protein localizes to both cytoplasm and nucleus, consistent with its roles in both CRL regulation and transcriptional regulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008180 COP9 signalosome | IBA GO_REF:0000033 | ACCEPT | Summary: Core annotation. COPS2/CSN2 is an integral subunit of the COP9 signalosome as demonstrated by multiple structural and biochemical studies. The CSN complex consists of COPS1-8/9 subunits, and COPS2 is part of the Csn1/2/3/8 module [PMID:19141280]. Crystal structure confirms COPS2 as a core subunit [PMID:25043011]. Reason: COPS2 is a well-established core subunit of the COP9 signalosome. IBA annotation based on phylogenetic inference is fully supported by extensive experimental evidence in mammals and other eukaryotes. Supporting Evidence: PMID:19141280 Our results indicate that the catalytically active human complex, reconstituted in vitro, is composed of a single copy of each of the eight subunits. By forming a total of 35 subcomplexes, we are able to build a comprehensive interaction map that shows two symmetrical modules, Csn1/2/3/8 and Csn4/5/6/7, connected by interactions between Csn1-Csn6. PMID:25043011 Here we present the crystal structure of the entire ∼350-kDa human CSN holoenzyme at 3.8 Å resolution, detailing the molecular architecture of the complex. |
| GO:0000338 protein deneddylation | IBA GO_REF:0000033 | ACCEPT | Summary: Core annotation. COPS2 is essential for CSN complex integrity and deneddylase function. Mouse knockout studies show that Csn2 disruption leads to loss of CSN function and accumulation of neddylated cullins [PMID:12628923]. The deneddylation is catalyzed by CSN5, but requires the intact complex including COPS2 for activity. Reason: COPS2 is required for CSN-mediated deneddylation. While COPS2 itself lacks catalytic activity (CSN5 is the isopeptidase), COPS2 is essential for CSN complex assembly and function. The IBA annotation appropriately captures the role of CSN2 in the deneddylation process. Supporting Evidence: PMID:25043011 CSN inactivates CRLs by removing their covalently attached activator, NEDD8. NEDD8 cleavage by CSN is catalysed by CSN5, a Zn(2+)-dependent isopeptidase that is inactive in isolation. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Supported by experimental evidence. CSN complex including COPS2 shows nuclear localization by fluorescence microscopy [PMID:24421388]. COPS2 as Alien/TRIP15 also functions in the nucleus as a corepressor for nuclear receptors [PMID:10207062]. Reason: IEA annotation is consistent with direct experimental evidence from multiple studies showing nuclear localization of COPS2 and the CSN complex. Supporting Evidence: PMID:24421388 Through biochemical and fluorescence microscopy analyses, we determined that the complex is localized in the cytoplasm, nucleoplasm, and chromatin-bound fractions, each differing in the composition of posttranslationally modified subunits, depending on its location within the cell |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Supported by experimental evidence. The CSN complex shows cytoplasmic localization [PMID:9535219, PMID:24421388]. Immunofluorescence staining reveals subcellular distribution similar to 26S proteasome. Reason: IEA annotation is consistent with direct experimental evidence showing cytoplasmic localization of COPS2/CSN2 and the CSN complex. Supporting Evidence: PMID:9535219 Immunofluorescence staining reveals that the new complex shows a subcellular distribution similar to that of the 26S proteasome. |
| GO:0008180 COP9 signalosome | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation above for same term. Both annotations are valid as they represent different evidence sources. Reason: IEA annotation consistent with extensive experimental data confirming COPS2 as a core subunit of the COP9 signalosome. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000117 | ACCEPT | Summary: Very general term. COPS2 is part of the COP9 signalosome complex, which is a more specific term already annotated. Reason: While GO:0008180 (COP9 signalosome) is more informative, this general complex annotation is not incorrect. COPS2 is indeed part of a protein-containing complex. |
| GO:0005515 protein binding | IPI PMID:15304329 Hepatopoietin interacts directly with COP9 signalosome and r... | MARK AS OVER ANNOTATED | Summary: Generic protein binding term. This annotation refers to hepatopoietin interaction with the COP9 signalosome. Too generic to be informative about COPS2 molecular function. Reason: Protein binding is too vague and uninformative. COPS2 has specific molecular functions as a scaffold protein and corepressor that are better captured by other terms. Supporting Evidence: PMID:15304329 Hepatopoietin interacts directly with COP9 signalosome and regulates AP-1 activity. |
| GO:0005515 protein binding | IPI PMID:18850735 Characterization of the human COP9 signalosome complex using... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from CSN complex characterization study. Identified protein-protein interactions via affinity purification and mass spectrometry. Reason: While the study confirms COPS2 interacts with other proteins within the CSN complex, the protein binding term is too generic. More specific scaffold or complex assembly terms would be more informative. Supporting Evidence: PMID:18850735 Characterization of the human COP9 signalosome complex using affinity purification and mass spectrometry. |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from deubiquitinating enzyme interaction landscape study - high-throughput study. Reason: High-throughput interactome study. Protein binding is too generic to be informative about COPS2 function. Supporting Evidence: PMID:19615732 Defining the human deubiquitinating enzyme interaction landscape. |
| GO:0005515 protein binding | IPI PMID:20399188 Structural insights into the COP9 signalosome and its common... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from structural study showing CSN architecture. This study provides important structural insights. Reason: While this study provides valuable structural information about CSN architecture, the protein binding annotation is too generic. Supporting Evidence: PMID:20399188 Structural insights into the COP9 signalosome and its common architecture with the 26S proteasome lid and eIF3. |
| GO:0005515 protein binding | IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from cullin-RING ligase network proteomics study - demonstrates COPS2/CSN interaction with CRL network. Reason: High-throughput proteomics study. Protein binding is uninformative as a molecular function annotation. Supporting Evidence: PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. |
| GO:0005515 protein binding | IPI PMID:21911577 A physical interaction network of dengue virus and human pro... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from dengue virus-human protein interaction network study. Reason: Viral interactome study. Protein binding is too generic and this interaction may represent viral hijacking rather than normal function. Supporting Evidence: PMID:21911577 A physical interaction network of dengue virus and human proteins. |
| GO:0005515 protein binding | IPI PMID:23441852 The corepressor activity of Alien is controlled by CREB-bind... | MODIFY | Summary: Protein binding documenting interaction between Alien/COPS2 and CREB-binding protein (CBP)/p300. This interaction controls corepressor activity through acetylation. Reason: This specific interaction with CBP/p300 relates to COPS2's corepressor function. A more informative term would capture the regulatory relationship between corepressor and coactivator. Proposed replacements: transcription corepressor activity Supporting Evidence: PMID:23441852 The corepressor Alien interacts with the CREB-binding protein (CBP) coactivator. This interaction was further confirmed by coimmunoprecipitation and glutathione S-transferase pull-down experiments, suggesting that Alien interacts in vivo and in vitro with the histone acetyltransferase (HAT) coactivators CBP and its paralog p300. |
| GO:0005515 protein binding | IPI PMID:24421388 Dynamic regulation of the COP9 signalosome in response to DN... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from CSN DNA damage response study. Study focuses on CSN complex dynamics rather than specific COPS2 interactions. Reason: High-throughput proteomics study. Protein binding is too generic. Supporting Evidence: PMID:24421388 Dynamic regulation of the COP9 signalosome in response to DNA damage. |
| GO:0005515 protein binding | IPI PMID:25043011 Crystal structure of the human COP9 signalosome. | MARK AS OVER ANNOTATED | Summary: Generic protein binding from CSN crystal structure study. This landmark study provides detailed structural information about CSN subunit interactions. Reason: While the structural study is highly valuable, protein binding is too generic as an MF annotation. COPS2's role as a structural scaffold is better captured by CC annotations. Supporting Evidence: PMID:25043011 Crystal structure of the human COP9 signalosome. |
| GO:0005515 protein binding | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from organelle-specific protein landscape study. Reason: High-throughput proteomics study. Protein binding is uninformative. Supporting Evidence: PMID:27173435 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic protein binding from human binary protein interactome reference map - large-scale interactome study. Reason: High-throughput interactome mapping. Protein binding is too generic. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from neurodegenerative disease interactome mapping study. Reason: High-throughput interactome study focused on neurodegeneration. Protein binding is uninformative. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from dual proteome-scale network study on human interactome remodeling. Reason: High-throughput proteomics study. Protein binding is uninformative. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from multimodal cell maps study on structural and functional genomics. Reason: High-throughput multimodal study. Protein binding is too generic. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: COPS2/Alien functions as a corepressor for nuclear hormone receptors including thyroid hormone receptor [PMID:10207062] and DAX-1 [PMID:10713076]. The corepressor activity is documented experimentally. Reason: IEA annotation consistent with experimental evidence. COPS2 as Alien/TRIP15 is a well-established corepressor for nuclear receptors, mediating transcriptional repression. Supporting Evidence: PMID:10207062 Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily. |
| GO:0003714 transcription corepressor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Core annotation for COPS2's Alien/TRIP15 function. Well-documented corepressor activity for nuclear hormone receptors including thyroid hormone receptor, DAX-1, and others [PMID:10207062, PMID:10713076, PMID:23441852]. Reason: IEA annotation consistent with extensive experimental evidence. COPS2 as Alien is a bona fide corepressor with documented ability to repress transcription in conjunction with nuclear receptors. Supporting Evidence: PMID:23441852 The regulation of gene repression by corepressors is a controlled process... the corepressor Alien interacts with the CREB-binding protein (CBP) coactivator. |
| GO:0030182 neuron differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: UniProt notes involvement in early stage of neuronal differentiation via interaction with NIF3L1. This is a downstream effect of CSN function or corepressor activity. Reason: While COPS2 may play a role in neuronal differentiation (possibly through its corepressor function or CSN activity), this is a downstream developmental effect rather than a core molecular function. |
| GO:0045171 intercellular bridge | IDA GO_REF:0000052 | UNDECIDED | Summary: This annotation from immunofluorescence data seems questionable for COPS2's known functions. The primary localization is nucleus and cytoplasm, not intercellular bridges. Reason: The evidence source GO_REF:0000052 refers to curation of immunofluorescence data, but intercellular bridge localization is not a well-characterized aspect of COPS2 function. Unable to access underlying data to verify. |
| GO:0005634 nucleus | IDA PMID:24421388 Dynamic regulation of the COP9 signalosome in response to DN... | ACCEPT | Summary: Direct evidence for nuclear localization from fluorescence microscopy analyses showing CSN complex in nucleoplasm and chromatin-bound fractions. Reason: Well-supported by direct experimental evidence in the cited publication. Supporting Evidence: PMID:24421388 Through biochemical and fluorescence microscopy analyses, we determined that the complex is localized in the cytoplasm, nucleoplasm, and chromatin-bound fractions, each differing in the composition of posttranslationally modified subunits, depending on its location within the cell |
| GO:0005737 cytoplasm | IDA PMID:24421388 Dynamic regulation of the COP9 signalosome in response to DN... | ACCEPT | Summary: Direct evidence for cytoplasmic localization from fluorescence microscopy and biochemical analyses. Reason: Well-supported by direct experimental evidence in the cited publication. Supporting Evidence: PMID:24421388 Through biochemical and fluorescence microscopy analyses, we determined that the complex is localized in the cytoplasm, nucleoplasm, and chromatin-bound fractions, each differing in the composition of posttranslationally modified subunits, depending on its location within the cell |
| GO:0045116 protein neddylation | NAS PMID:24421388 Dynamic regulation of the COP9 signalosome in response to DN... | MODIFY | Summary: The CSN complex primarily performs deneddylation (removal of NEDD8), not neddylation (addition of NEDD8). This annotation appears to be an error or misunderstanding of CSN function. Reason: The CSN complex, including COPS2, is involved in deneddylation, the opposite of neddylation. The term should be changed to reflect the regulatory role or the correct process. Proposed replacements: protein deneddylation Supporting Evidence: PMID:25043011 CSN inactivates CRLs by removing their covalently attached activator, NEDD8. |
| GO:2000434 regulation of protein neddylation | NAS PMID:24421388 Dynamic regulation of the COP9 signalosome in response to DN... | ACCEPT | Summary: CSN regulates the neddylation/deneddylation cycle by performing deneddylation, thereby controlling CRL activity. This annotation captures the regulatory aspect appropriately. Reason: The CSN complex does regulate protein neddylation levels by catalyzing deneddylation. This annotation appropriately captures the regulatory role of the complex in the neddylation cycle. Supporting Evidence: PMID:25043011 CSN inactivates CRLs by removing their covalently attached activator, NEDD8. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate of IEA annotation for same term. ISS evidence from sequence similarity supports the corepressor function. Reason: Consistent with COPS2/Alien's documented corepressor function. |
| GO:0006468 protein phosphorylation | IDA PMID:9535219 A novel protein complex involved in signal transduction poss... | MODIFY | Summary: OVER-ANNOTATION: COPS2 is a PCI-domain scaffold subunit of the COP9 signalosome (CSN). PMID:9535219 shows the CSN complex has kinase activity, but UniProt notes this is "possibly via its association with CK2 and PKD kinases". COPS2 itself lacks kinase catalytic activity - it is a structural scaffold. The kinase activity comes from associated kinases, not COPS2. Reason: COPS2 does not have intrinsic kinase activity. The phosphorylation activity is due to associated kinases (CK2, PKD) that interact with the CSN complex. The annotation should reflect the regulatory role rather than direct catalytic phosphorylation. Proposed replacements: regulation of protein kinase activity Supporting Evidence: PMID:9535219 The isolated JAB1-containing particle has kinase activity that phosphorylates IkappaBalpha, the carboxy terminus of p105, and Ser63 and/or Ser73 of the amino-terminal activation domain of c-Jun. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8863721 | ACCEPT | Summary: Reactome annotation for CSN involvement in TOR1/STON deneddylation pathway. Cytosolic localization is consistent with biochemical evidence. Reason: Consistent with experimental evidence showing cytoplasmic/cytosolic localization of the CSN complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8863723 | ACCEPT | Summary: Reactome annotation for COP9 and TOR1 deneddylation activity. Duplicate localization annotation for same compartment. Reason: Consistent with known cytosolic localization of CSN complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: Reactome annotation for CSN deneddylation of cytosolic CRL E3 ubiquitin ligase complexes. Reason: Appropriate annotation reflecting cytosolic location of CSN-CRL deneddylation activity. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5691006 | ACCEPT | Summary: Reactome annotation for XPC:RAD23:CETN2 and UV-DDB binding to distorted DNA in nucleotide excision repair context. Reason: CSN complex has documented nucleoplasmic localization and role in DNA damage response [PMID:24421388]. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6781833 | ACCEPT | Summary: Reactome annotation for ERCC8 (CSA) binding stalled RNA Pol II, relevant to transcription-coupled repair. Reason: CSN complex localizes to nucleoplasm and participates in DNA damage response pathways. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8956045 | ACCEPT | Summary: Reactome annotation for CSN deneddylation of nuclear CRL4 E3 ubiquitin ligase complex. Reason: Appropriate annotation reflecting nucleoplasmic location of CSN-CRL4 deneddylation activity in DNA repair contexts. |
| GO:0000338 protein deneddylation | IDA PMID:19141280 Symmetrical modularity of the COP9 signalosome complex sugge... | ACCEPT | Summary: Direct evidence for deneddylation function. Study reconstituted catalytically active CSN complex in vitro and demonstrated deneddylation activity. Reason: Well-supported by direct experimental evidence. COPS2 as part of the reconstituted CSN complex is essential for deneddylation. Supporting Evidence: PMID:19141280 Our results indicate that the catalytically active human complex, reconstituted in vitro, is composed of a single copy of each of the eight subunits. |
| GO:0008180 COP9 signalosome | IDA PMID:18850735 Characterization of the human COP9 signalosome complex using... | ACCEPT | Summary: Direct identification of COPS2 as CSN subunit by affinity purification and mass spectrometry. Reason: Strong experimental evidence confirming COPS2 as a component of the CSN complex. Supporting Evidence: PMID:18850735 Mass spectrometric analysis of the purified CSN complex has revealed the identity of its composition as well as N-terminal modification and phosphorylation of the CSN subunits |
| GO:0005515 protein binding | IPI PMID:17438371 Detection and identification of transcription factors as int... | MODIFY | Summary: Study identified transcription factors as interaction partners of Alien/COPS2 including nucleophosmin, ERCC3, TRIP11, and CRSP3. These interactions relate to COPS2's role in transcriptional regulation and DNA repair. Reason: The interactions identified are more informative than generic protein binding. The interactions with transcription factors support the corepressor activity annotation. Proposed replacements: transcription corepressor activity Supporting Evidence: PMID:17438371 In this way we detected protein interactions of Alien involving nucleophosmin, ERCC3, TRIP11, as well as CRSP3 |
| GO:0005737 cytoplasm | IDA PMID:9535219 A novel protein complex involved in signal transduction poss... | ACCEPT | Summary: Early characterization of CSN showing cytoplasmic distribution by immunofluorescence. Reason: Well-supported by direct experimental evidence. Supporting Evidence: PMID:9535219 Immunofluorescence staining reveals that the new complex shows a subcellular distribution similar to that of the 26S proteasome. |
| GO:0006366 transcription by RNA polymerase II | TAS PMID:7776974 Two classes of proteins dependent on either the presence or ... | MODIFY | Summary: Early study identified TRIP15/COPS2 as thyroid hormone receptor- interacting protein, implying role in transcription. The general transcription term is broader than the specific corepressor role. Reason: COPS2/TRIP15's role in transcription is specifically as a corepressor, not a general transcription factor. A more specific term is appropriate. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:7776974 Several such proteins, called Trips (TR-interacting proteins), were isolated from independent selections carried out either in the presence or absence of T3. |
| GO:0007165 signal transduction | NAS PMID:9535219 A novel protein complex involved in signal transduction poss... | KEEP AS NON CORE | Summary: The original CSN characterization paper proposed signaling roles based on kinase activity and substrate phosphorylation. This is a very broad term. Reason: Signal transduction is a downstream effect of CSN function in regulating CRL-mediated proteolysis and associated kinase activity. Not a core molecular function of COPS2. Supporting Evidence: PMID:9535219 Considering the putative role of the complex in signal transduction and its widespread occurrence, we suggest the name JAB1-containing signalosome. |
| GO:0008180 COP9 signalosome | IDA PMID:9535219 A novel protein complex involved in signal transduction poss... | ACCEPT | Summary: Original characterization study identifying COPS2/TRIP15 as a subunit of the novel CSN complex. Reason: Foundational experimental evidence establishing COPS2 as a CSN subunit. Supporting Evidence: PMID:9535219 It consists of at least eight different subunits including JAB1, the Jun activation-domain binding protein 1, and Trip15, the thyroid hormone receptor-interacting protein 15. |
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