id: Q9H000 gene_symbol: MKRN2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- MKRN2 (makorin RING finger protein 2; RNF62) is a RING-type E3 ubiquitin ligase of the makorin family and a paralog of MKRN1. Like other makorins it pairs a C3HC4 RING domain, which confers ubiquitin-protein ligase activity, with CCCH/C3H zinc-finger motifs capable of RNA binding. MKRN2 catalyzes ubiquitin transfer onto substrate proteins; it has been reported (largely by similarity to the rodent ortholog) to promote polyubiquitination and proteasome-dependent degradation of the NF-kB subunit RELA/p65, thereby suppressing RELA-mediated transactivation and dampening inflammatory responses, and to contribute to spermiation and male fertility. It is found in both the cytoplasm and nucleus. MKRN2 is considerably less characterized than MKRN1, and many of its biological-process annotations derive from cross-species inference rather than direct human experimentation. existing_annotations: - term: id: GO:0016567 label: protein ubiquitination evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: >- MKRN2 is a makorin RING E3 ligase that ubiquitinates substrate proteins. Core process, phylogenetically and structurally supported. action: ACCEPT reason: >- The makorin RING domain confers E3 ligase activity; protein ubiquitination is the core biological process. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: >- Core molecular function: MKRN2 is a RING-type ubiquitin-protein ligase. action: ACCEPT reason: >- RING domain and family membership support E3 ligase activity (EC 2.3.2.27). supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0000209 label: protein polyubiquitination evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: >- MKRN2 polyubiquitinates substrates (e.g. RELA/p65) for proteasomal degradation. action: ACCEPT reason: >- Consistent with E3 ligase activity and reported RELA degradation. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: >- Nuclear localization (IEA). Consistent with roles in transcriptional regulation and RELA ubiquitination; corroborated by ISS. action: ACCEPT reason: >- MKRN2 is reported in both nucleus and cytoplasm. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: >- Cytoplasmic localization (IEA). Consistent with cytoplasmic E3 ligase activity. action: ACCEPT reason: >- MKRN2 is reported in both cytoplasm and nucleus. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0046872 label: metal ion binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- MKRN2 has a C3HC4 RING and CCCH zinc fingers that coordinate zinc. Generic metal-ion binding underlies these motifs. action: KEEP_AS_NON_CORE reason: >- Zinc coordination is structurally required; the informative functions are E3 ligase activity and RNA binding. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: >- Duplicate (electronic) annotation of the core E3 ligase MF. action: ACCEPT reason: >- Consistent with the RING E3 ligase function. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17500595 qualifier: enables review: summary: >- Generic protein-binding annotation from a Huntingtin-interacting-protein genetic modifier screen. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- High-throughput interaction screen; no specific functional insight for MKRN2. supported_by: - reference_id: PMID:17500595 supporting_text: Huntingtin interacting proteins are genetic modifiers of neurodegeneration. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22046132 qualifier: enables review: summary: >- Generic protein-binding annotation from a SARS-coronavirus host interactome study. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- High-throughput virus-host interactome; no specific functional insight. supported_by: - reference_id: PMID:22046132 supporting_text: The SARS-coronavirus-host interactome - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: >- Generic protein-binding annotation from the HI-III human interactome (Y2H). Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- Large-scale interactome screen; no specific functional insight. supported_by: - reference_id: PMID:25416956 supporting_text: A proteome-scale map of the human interactome network. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: >- Generic protein-binding annotation from the HuRI binary interactome. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- High-throughput Y2H interactome; no specific functional insight. supported_by: - reference_id: PMID:32296183 supporting_text: A reference map of the human binary protein interactome. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: >- Generic protein-binding annotation from a neurodegenerative-disease interactome study. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- High-throughput interactome dataset; no specific functional insight. supported_by: - reference_id: PMID:32814053 supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32838362 qualifier: enables review: summary: >- Generic protein-binding annotation from a virus-host interactome/proteomic survey. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- High-throughput virus-host interactome; no specific functional insight. supported_by: - reference_id: PMID:32838362 supporting_text: Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36217029 qualifier: enables review: summary: >- Generic protein-binding annotation from the SARS-CoV-2-human contactome. Uninformative as a molecular function. action: KEEP_AS_NON_CORE reason: >- High-throughput virus-host contactome; no specific functional insight. supported_by: - reference_id: PMID:36217029 supporting_text: A proteome-scale map of the SARS-CoV-2-human contactome. - term: id: GO:0002862 label: negative regulation of inflammatory response to antigenic stimulus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- MKRN2 (via RELA/p65 degradation) is inferred to negatively regulate inflammatory responses. Ortholog-based inference. action: KEEP_AS_NON_CORE reason: >- Plausible consequence of RELA ubiquitination but based on cross-species inference, not direct human evidence; retained as non-core. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- MKRN2 targets substrates (RELA/p65) for proteasomal degradation via ubiquitination. action: ACCEPT reason: >- Consistent with E3 ligase activity driving proteasomal degradation of substrates. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation - term: id: GO:1901223 label: negative regulation of non-canonical NF-kappaB signal transduction evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- MKRN2 is inferred to negatively regulate NF-kB signaling via RELA/p65 degradation. The UniProt statement concerns RELA-mediated (canonical) NF-kB transactivation; the 'non-canonical' specificity may be imprecise. action: KEEP_AS_NON_CORE reason: >- RELA/p65 is a canonical NF-kB subunit; the negative-regulation role is plausible but ortholog-inferred and the non-canonical qualifier is not clearly supported. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: >- Electronic annotation of protein ubiquitination (UniProt keyword). Supported. action: ACCEPT reason: >- Consistent with MKRN2's E3 ligase activity. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0005634 label: nucleus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: >- Nuclear localization (ISS from ortholog). Consistent with nuclear RELA/transcription roles. action: KEEP_AS_NON_CORE reason: >- Ortholog-based; consistent with cytoplasmic+nuclear distribution. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0005737 label: cytoplasm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: >- Cytoplasmic localization (ISS from ortholog). action: ACCEPT reason: >- Consistent with cytoplasmic E3 ligase activity. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: >- Core E3 ligase MF (ISS from ortholog). Supported. action: ACCEPT reason: >- Consistent with RING E3 ligase activity. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0002862 label: negative regulation of inflammatory response to antigenic stimulus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- Negative regulation of inflammation via RELA degradation (ISS). Ortholog-based. action: KEEP_AS_NON_CORE reason: >- Plausible but cross-species inferred; retained as non-core. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- Ubiquitin-dependent degradation of substrates (ISS). Supported by E3 ligase activity. action: ACCEPT reason: >- Consistent with proteasome-dependent degradation of RELA/p65. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation - term: id: GO:1901223 label: negative regulation of non-canonical NF-kappaB signal transduction evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- Negative regulation of NF-kB via RELA degradation (ISS). The 'non-canonical' qualifier may be imprecise given RELA is a canonical-pathway subunit. action: KEEP_AS_NON_CORE reason: >- Ortholog-inferred; non-canonical specificity not clearly supported. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation - term: id: GO:0006351 label: DNA-templated transcription evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- Broad 'DNA-templated transcription' involvement (ISS). MKRN2 is an E3 ligase; any transcriptional effect is indirect (via substrate degradation). The term is overly broad and not directly supported. action: MARK_AS_OVER_ANNOTATED reason: >- MKRN2 is not a transcription factor; its influence on transcription is indirect through ubiquitination of regulators. The generic transcription term over-states a direct role. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0043491 label: phosphatidylinositol 3-kinase/protein kinase B signal transduction evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- PI3K/AKT signaling involvement (ISS from ortholog). Indirect and weakly supported for human MKRN2. action: KEEP_AS_NON_CORE reason: >- Cross-species inference; retained as non-core pending direct human evidence. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- Positive regulation of Pol II transcription (ISS). For an E3 ligase this is an indirect effect; the term over-states a direct transcriptional role. action: MARK_AS_OVER_ANNOTATED reason: >- MKRN2 is not a transcriptional coactivator; any positive effect on transcription is indirect via substrate ubiquitination. supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: E3 ubiquitin-protein ligase makorin-2 - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22681889 qualifier: enables review: summary: >- RNA binding (mRNA interactome capture). MKRN2 contains CCCH zinc fingers; RNA binding is consistent with the makorin family. Genuine. action: ACCEPT reason: >- MKRN2 was identified as an mRNA-binding protein, consistent with its CCCH zinc fingers. supported_by: - reference_id: file:human/MKRN2/MKRN2-goa.tsv supporting_text: PMID:22681889 core_functions: - description: >- MKRN2 is a makorin-family RING-type E3 ubiquitin-protein ligase that catalyzes ubiquitin transfer onto substrate lysines, targeting substrates (including the NF-kB subunit RELA/p65) for proteasome-dependent degradation. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity locations: - id: GO:0005737 label: cytoplasm - id: GO:0005634 label: nucleus supported_by: - reference_id: file:human/MKRN2/MKRN2-uniprot.txt supporting_text: RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation - description: >- MKRN2 is an RNA-binding protein via its CCCH zinc fingers, consistent with the makorin family's coupling of RNA recognition to ubiquitin ligase activity. molecular_function: id: GO:0003723 label: RNA binding locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/MKRN2/MKRN2-goa.tsv supporting_text: PMID:22681889 proposed_new_terms: [] suggested_questions: - question: Does human MKRN2 directly ubiquitinate RELA/p65 and regulate NF-kB/inflammation, or are these roles confined to the rodent ortholog? - question: Given the makorin family's role in poly(A) ribosome-associated quality control (MKRN1), does MKRN2 contribute to co-translational quality control, and how is it functionally partitioned from MKRN1? suggested_experiments: - description: In vitro and cell-based ubiquitination assays with human MKRN2 (and a RING-dead mutant) on candidate substrates (RELA/p65, ribosome-associated proteins) to establish direct activity. - description: iCLIP/ribosome profiling in MKRN2-knockout human cells to test for a poly(A)/RQC role analogous to MKRN1 and define MKRN2-specific target transcripts. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:17500595 title: Huntingtin interacting proteins are genetic modifiers of neurodegeneration. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: High-throughput huntingtin interactome screen; a passing/contextual capture of MKRN2, not informative about its core molecular function. Not cached; relevance to MKRN2 function is low. - id: PMID:22046132 title: 'The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors.' findings: [] - id: PMID:22681889 title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Cached publication title matches the YAML title; GOA anchors this PMID to HDA for GO:0003723 (RNA binding). It is a global mRNA-interactome screen, not a dedicated MKRN2 study, so it supports (but does not by itself establish) the RNA-binding core function. No dedicated experimental paper establishes human MKRN2's core E3 ligase activity in this review. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:32838362 title: Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis. findings: [] - id: PMID:36217029 title: A proteome-scale map of the SARS-CoV-2-human contactome. findings: [] - id: file:human/MKRN2/MKRN2-uniprot.txt title: UniProt entry Q9H000 (MKRN2_HUMAN) findings: [] - id: file:human/MKRN2/MKRN2-goa.tsv title: GOA annotations for MKRN2 findings: []