MKRN2

UniProt ID: Q9H000
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

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

Core Functions

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:
ubiquitin protein ligase activity
Cellular Locations:
cytoplasm nucleus
Supporting Evidence:
  • file:human/MKRN2/MKRN2-uniprot.txt
    RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation

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:
RNA binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/MKRN2/MKRN2-goa.tsv
    PMID:22681889

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:17500595
Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
PMID:22046132
The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors.
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:32838362
Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis.
PMID:36217029
A proteome-scale map of the SARS-CoV-2-human contactome.
file:human/MKRN2/MKRN2-uniprot.txt
UniProt entry Q9H000 (MKRN2_HUMAN)
file:human/MKRN2/MKRN2-goa.tsv
GOA annotations for MKRN2

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(MKRN2-notes.md)

MKRN2 (Q9H000) research notes

Makorin RING finger protein 2 (RNF62). RING-type E3 ubiquitin ligase, makorin family
(paralog of MKRN1). Contains C3HC4 RING and CCCH/C3H zinc fingers (RNA-binding). Less
characterized than MKRN1; most functional assignments are By similarity / ISS from the
mouse ortholog (Q9ERV1).

Core MF: RING E3 ubiquitin ligase

UniProt: "E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto
substrate proteins (By similarity). Promotes the polyubiquitination and proteasome-dependent
degradation of RELA/p65, thereby suppressing RELA-mediated NF-kappaB transactivation and
negatively regulating inflammatory responses (By similarity). Plays a role in the regulation
of spermiation and in male fertility (By similarity)." CATALYTIC EC=2.3.2.27 (by similarity).
RING domain (CDD RING-HC_MKRN2).

Substrate / signaling (ISS / by similarity)

  • RELA/p65 polyubiquitination -> negative regulation of NF-kB / inflammatory response
    (GO:1901223, GO:0002862, GO:0006511). ISS from GO_REF:0000024 (ortholog transfer).
  • PI3K/AKT signaling, transcription regulation, spermiation — ISS, ortholog-based.

RNA binding

GO:0003723 RNA binding (HDA, PMID:22681889) — consistent with CCCH zinc fingers; genuine.

protein binding IPI (all HT / virus-host)

  • PMID:17500595 Huntingtin interacting proteins (HT screen)
  • PMID:22046132 SARS-coronavirus-host interactome
  • PMID:25416956 HI-III human interactome (Y2H)
  • PMID:32296183 HuRI binary interactome
  • PMID:32814053 neurodegenerative disease interactome
  • PMID:32838362 virus-host interactome (virulence factors)
  • PMID:36217029 SARS-CoV-2-human contactome
    -> all KEEP_AS_NON_CORE / MARK_AS_OVER_ANNOTATED.

Annotation plan

  • GO:0061630 ubiquitin protein ligase activity (IBA/IEA/ISS): ACCEPT (core MF, makorin RING).
  • GO:0016567 protein ubiquitination / GO:0000209 polyubiquitination / GO:0006511 ubiquitin-
    dependent catabolic process: ACCEPT.
  • GO:0046872 metal ion binding (IEA): KEEP_AS_NON_CORE (Zn coordination).
  • NF-kB / inflammatory / RELA terms (ISS): KEEP_AS_NON_CORE (ortholog-based, plausible but not
    directly demonstrated in human).
  • transcription terms (DNA-templated transcription, pos reg pol II), PI3K/AKT (ISS): KEEP_AS_NON_CORE
    or MARK_AS_OVER_ANNOTATED (broad, ortholog-transferred, weakly supported).
  • nucleus/cytoplasm localization: ACCEPT/KEEP_AS_NON_CORE.
  • GO:0003723 RNA binding (HDA): ACCEPT.
    Note: unlike MKRN1, there is no direct evidence (in the available set) for an MKRN2-specific
    poly(A)-RQC role; the family RQC role is noted but should not be over-asserted for MKRN2.

Pn Notes

(MKRN2-pn-notes.md)

MKRN2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9H000
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 12; KEEP_AS_NON_CORE: 14; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

  • Consistency: Partial mismatch. The UPS/E3-ligase placement (GO:0061630, GO:0016567) matches the review perfectly — both already in GOA (IBA/IEA/ISS). BUT the PN puts MKRN2 in the same RQC node as MKRN1, projecting GO:0006515 (protein QC). The review finds no direct or inferred RQC evidence for human MKRN2 — RQC is raised only as a suggested question ("does MKRN2 contribute to co-translational QC… how is it partitioned from MKRN1?"). MKRN2's characterized biology is RELA/p65 / NF-kB (mostly ISS/by-similarity from rodent), not poly(A) RQC. So the PN RQC placement for MKRN2 is paralogy-driven over-reach, inherited from MKRN1.
  • PN story / NEW pressure: No defensible NEW pressure. There is no human-experimental basis to annotate MKRN2 to GO:0006515 or GO:1990116; doing so would be PARALOG_OVERANNOTATION (MKRN1 evidence applied to MKRN2). The review correctly withholds an RQC annotation. The genuine MKRN2 functions (E3 ligase, NF-kB regulation) are already captured/over-annotation-flagged.
  • Evidence alignment: PN row 2 cites "19489725 / rev" (makorin review, same as MKRN1). Review anchors only on RNA-binding screen PMID:22681889 (HDA, VERIFIED) plus uniprot/ISS; notably no dedicated experimental paper establishes human MKRN2's E3 activity or any RQC role — consistent with the review's caution. Divergence: PN asserts RQC; review evidence does not.
  • Verdict: Over-reach on the RQC branch (paralog inheritance from MKRN1). E3-ligase placement consistent. Recommended edits: [MAP] do not project GO:0006515 / GO:1990116 onto MKRN2 from the RQC node — no human-experimental RQC evidence; flag MKRN2's RQC-node membership as paralogy-driven (PARALOG_OVERANNOTATION) pending the suggested iCLIP/ribosome-profiling experiment.

Full Consistency Review

  • UniProt: Q9H000 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: two rows — Translation|Cytosolic translation|Ribosome-associated QC|Ubiquitination (TR) and UPS|E3 ubiquitin and UBL ligases|RING|Makorin|C3H1-type ZnF (UPS). PN-node mapping: identical to MKRN1 — RQC type→GO:0016567 (mapped); RQC group→GO:0006515 (mapped); RING group→GO:0061630 (mapped); subtype + UPS branch = no_mapping.
  • Consistency: Partial mismatch. The UPS/E3-ligase placement (GO:0061630, GO:0016567) matches the review perfectly — both already in GOA (IBA/IEA/ISS). BUT the PN puts MKRN2 in the same RQC node as MKRN1, projecting GO:0006515 (protein QC). The review finds no direct or inferred RQC evidence for human MKRN2 — RQC is raised only as a suggested question ("does MKRN2 contribute to co-translational QC… how is it partitioned from MKRN1?"). MKRN2's characterized biology is RELA/p65 / NF-kB (mostly ISS/by-similarity from rodent), not poly(A) RQC. So the PN RQC placement for MKRN2 is paralogy-driven over-reach, inherited from MKRN1.
  • PN story / NEW pressure: No defensible NEW pressure. There is no human-experimental basis to annotate MKRN2 to GO:0006515 or GO:1990116; doing so would be PARALOG_OVERANNOTATION (MKRN1 evidence applied to MKRN2). The review correctly withholds an RQC annotation. The genuine MKRN2 functions (E3 ligase, NF-kB regulation) are already captured/over-annotation-flagged.
  • Mapping strategy: This gene should NOT inherit the RQC-group GO:0006515 projection. The node mapping is fine as a bucket for MKRN1, but MKRN2's membership in that node is the problem — its projected GO:0006515 is unsupported for this paralog. Flag: MKRN2 RQC placement is broader/unsupported relative to the review (which has zero RQC terms).
  • Evidence alignment: PN row 2 cites "19489725 / rev" (makorin review, same as MKRN1). Review anchors only on RNA-binding screen PMID:22681889 (HDA, VERIFIED) plus uniprot/ISS; notably no dedicated experimental paper establishes human MKRN2's E3 activity or any RQC role — consistent with the review's caution. Divergence: PN asserts RQC; review evidence does not.
  • Verdict: Over-reach on the RQC branch (paralog inheritance from MKRN1). E3-ligase placement consistent. Recommended edits: [MAP] do not project GO:0006515 / GO:1990116 onto MKRN2 from the RQC node — no human-experimental RQC evidence; flag MKRN2's RQC-node membership as paralogy-driven (PARALOG_OVERANNOTATION) pending the suggested iCLIP/ribosome-profiling experiment.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/MKRN2/MKRN2-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | Ubiquitination

  • UniProt: Q9H000
  • In branches: TR, UPS
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|Ubiquitination
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0016567 protein ubiquitination]
      rationale: This PN RQC type denotes ubiquitination events on stalled translation complexes. Protein ubiquitination is the shared process target.
    • [group] Translation|Cytosolic translation|Ribosome-associated QC
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
      rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | Makorin | C3H1-type ZnF

  • UniProt: Q9H000
  • In branches: TR, UPS
  • Signature domains: IPR001841
  • Auxiliary domains: IPR000571
  • PN references (titles):
    • 19489725 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|Makorin|C3H1-type ZnF
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|Makorin
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (3)

  • GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
  • GO:0016567 protein ubiquitination | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Ribosome-associated QC|Ubiquitination
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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: []