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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016567 protein ubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: MKRN2 is a makorin RING E3 ligase that ubiquitinates substrate proteins. Core process, phylogenetically and structurally supported. Reason: The makorin RING domain confers E3 ligase activity; protein ubiquitination is the core biological process. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function: MKRN2 is a RING-type ubiquitin-protein ligase. Reason: RING domain and family membership support E3 ligase activity (EC 2.3.2.27). Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0000209 protein polyubiquitination | IEA GO_REF:0000002 | ACCEPT | Summary: MKRN2 polyubiquitinates substrates (e.g. RELA/p65) for proteasomal degradation. Reason: Consistent with E3 ligase activity and reported RELA degradation. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization (IEA). Consistent with roles in transcriptional regulation and RELA ubiquitination; corroborated by ISS. Reason: MKRN2 is reported in both nucleus and cytoplasm. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic localization (IEA). Consistent with cytoplasmic E3 ligase activity. Reason: MKRN2 is reported in both cytoplasm and nucleus. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: MKRN2 has a C3HC4 RING and CCCH zinc fingers that coordinate zinc. Generic metal-ion binding underlies these motifs. Reason: Zinc coordination is structurally required; the informative functions are E3 ligase activity and RNA binding. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate (electronic) annotation of the core E3 ligase MF. Reason: Consistent with the RING E3 ligase function. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0005515 protein binding | IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from a Huntingtin-interacting-protein genetic modifier screen. Uninformative as a molecular function. Reason: High-throughput interaction screen; no specific functional insight for MKRN2. Supporting Evidence: PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neurodegeneration. |
| GO:0005515 protein binding | IPI PMID:22046132 The SARS-coronavirus-host interactome: identification of cyc... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from a SARS-coronavirus host interactome study. Uninformative as a molecular function. Reason: High-throughput virus-host interactome; no specific functional insight. Supporting Evidence: PMID:22046132 The SARS-coronavirus-host interactome |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Generic protein-binding annotation from the HI-III human interactome (Y2H). Uninformative as a molecular function. Reason: Large-scale interactome screen; no specific functional insight. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Generic protein-binding annotation from the HuRI binary interactome. Uninformative as a molecular function. Reason: High-throughput Y2H interactome; no specific functional insight. 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 ... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from a neurodegenerative-disease interactome study. Uninformative as a molecular function. Reason: High-throughput interactome dataset; no specific functional insight. 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:32838362 Virus-Host Interactome and Proteomic Survey Reveal Potential... | KEEP AS NON CORE | Summary: Generic protein-binding annotation from a virus-host interactome/proteomic survey. Uninformative as a molecular function. Reason: High-throughput virus-host interactome; no specific functional insight. Supporting Evidence: PMID:32838362 Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors |
| GO:0005515 protein binding | IPI PMID:36217029 A proteome-scale map of the SARS-CoV-2-human contactome. | KEEP AS NON CORE | Summary: Generic protein-binding annotation from the SARS-CoV-2-human contactome. Uninformative as a molecular function. Reason: High-throughput virus-host contactome; no specific functional insight. Supporting Evidence: PMID:36217029 A proteome-scale map of the SARS-CoV-2-human contactome. |
| GO:0002862 negative regulation of inflammatory response to antigenic stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: MKRN2 (via RELA/p65 degradation) is inferred to negatively regulate inflammatory responses. Ortholog-based inference. Reason: Plausible consequence of RELA ubiquitination but based on cross-species inference, not direct human evidence; retained as non-core. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: MKRN2 targets substrates (RELA/p65) for proteasomal degradation via ubiquitination. Reason: Consistent with E3 ligase activity driving proteasomal degradation of substrates. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation |
| GO:1901223 negative regulation of non-canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: Electronic annotation of protein ubiquitination (UniProt keyword). Supported. Reason: Consistent with MKRN2's E3 ligase activity. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nuclear localization (ISS from ortholog). Consistent with nuclear RELA/transcription roles. Reason: Ortholog-based; consistent with cytoplasmic+nuclear distribution. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Cytoplasmic localization (ISS from ortholog). Reason: Consistent with cytoplasmic E3 ligase activity. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0061630 ubiquitin protein ligase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Core E3 ligase MF (ISS from ortholog). Supported. Reason: Consistent with RING E3 ligase activity. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0002862 negative regulation of inflammatory response to antigenic stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of inflammation via RELA degradation (ISS). Ortholog-based. Reason: Plausible but cross-species inferred; retained as non-core. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation |
| GO:0006511 ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Ubiquitin-dependent degradation of substrates (ISS). Supported by E3 ligase activity. Reason: Consistent with proteasome-dependent degradation of RELA/p65. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation |
| GO:1901223 negative regulation of non-canonical NF-kappaB signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of NF-kB via RELA degradation (ISS). The 'non-canonical' qualifier may be imprecise given RELA is a canonical-pathway subunit. Reason: Ortholog-inferred; non-canonical specificity not clearly supported. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation |
| GO:0006351 DNA-templated transcription | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: PI3K/AKT signaling involvement (ISS from ortholog). Indirect and weakly supported for human MKRN2. Reason: Cross-species inference; retained as non-core pending direct human evidence. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | 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. Reason: MKRN2 is not a transcriptional coactivator; any positive effect on transcription is indirect via substrate ubiquitination. Supporting Evidence: file:human/MKRN2/MKRN2-uniprot.txt E3 ubiquitin-protein ligase makorin-2 |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | ACCEPT | Summary: RNA binding (mRNA interactome capture). MKRN2 contains CCCH zinc fingers; RNA binding is consistent with the makorin family. Genuine. Reason: MKRN2 was identified as an mRNA-binding protein, consistent with its CCCH zinc fingers. Supporting Evidence: file:human/MKRN2/MKRN2-goa.tsv PMID:22681889 |
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Download this section (compressed HTML)Q: Does human MKRN2 directly ubiquitinate RELA/p65 and regulate NF-kB/inflammation, or are these roles confined to the rodent ortholog?
Q: 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?
Experiment: 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.
Experiment: 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.
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