| 2017 |
MKRN2 is a RING finger domain-dependent E3 ubiquitin ligase that binds to the p65 subunit of NF-κB, promotes its K48-linked polyubiquitination and proteasome-dependent degradation, thereby suppressing NF-κB transactivation. MKRN2 was identified via yeast two-hybrid screening with PDLIM2, and MKRN2 and PDLIM2 synergistically promote p65 polyubiquitination and degradation. MKRN2 knockdown in dendritic cells increased nuclear p65 and augmented proinflammatory cytokine production. |
Yeast two-hybrid screening, Co-IP, in vitro ubiquitination assay, RING domain mutagenesis, shRNA knockdown, cytokine measurement |
Scientific reports |
High |
28378844
|
| 2008 |
Xenopus makorin-2 (mkrn2) functions as a neurogenesis inhibitor acting downstream of PI3K and Akt and upstream of GSK-3β; overexpression suppresses PI3K/Akt-induced neural marker (NCAM) expression and upregulates GSK-3β mRNA and protein, while morpholino knockdown induces double axis in tadpoles. |
Xenopus animal cap explant assay, morpholino antisense knockdown, overexpression of constitutively active PI3K/Akt and dominant negative GSK-3β, Western blot, RT-PCR |
The Journal of biological chemistry |
High |
18198183
|
| 2010 |
The third C3H zinc finger, Cys-His motif, and C3HC4 RING zinc finger of mkrn2 are essential and sufficient for its anti-neurogenic activity; a C-terminal truncation mutant containing only these domains (mkrn2(s)-7) recapitulates the full-length phenotype of dorso-posterior deficiencies in tadpoles and inhibits NCAM expression and induces GSK-3β in animal cap assays. |
N- and C-terminal truncation mutagenesis, Xenopus overexpression, animal cap explant assay |
Biochemical and biophysical research communications |
Medium |
20167204
|
| 2016 |
Mkrn2 knockout in mice causes male infertility characterized by low sperm number, poor motility, aberrant morphology, spermiation failure, and misarrangement of ectoplasmic specialization in testes; mechanistically, Odf2 (a vital spermatogenesis protein) expression is significantly decreased in knockout testes. |
Mkrn2 knockout mouse model, histology, sperm analysis, Western blot for Odf2 |
Scientific reports |
High |
28008940
|
| 2020 |
Mkrn2 deficiency in mice causes abnormally high testicular apoptosis through the p53/PERP signaling pathway; MKRN2 normally suppresses PERP expression, and PERP acts as a negative regulator of spermatogenesis whose ectopic expression induces male infertility. |
Mkrn2 knockout mouse model, digital gene expression profiling (DGE), GSEA, KEGG pathway analysis, protein expression analysis |
Asian journal of andrology |
Medium |
31489847
|
| 2020 |
MKRN2 ubiquitinates IGF2BP3 (an RNA-binding protein) to promote its degradation, thereby regulating CD44 and PDPN expression; MKRN2 knockdown in neuroblastoma SHSY5Y cells promotes proliferation and migration in an IGF2BP3-dependent manner. |
shRNA knockdown, Co-IP, pulldown, in vitro ubiquitination assay, Western blot |
Biochemical and biophysical research communications |
Medium |
32560817
|
| 2020 |
MKRN2 interacts with and ubiquitinates p53 to promote its degradation, thereby regulating melanoma cell proliferation; MKRN2 downregulation inhibits melanoma cell growth in a p53-dependent manner (confirmed by p53 CRISPR knockout rescue). |
Co-IP, GST pulldown, in vitro ubiquitination assay, CRISPR-Cas9 p53 knockout, MTT and colony formation assays |
Oncology letters |
High |
32194692
|
| 2020 |
MKRN2 physically interacts with GLE1 (a DEAD-box helicase activator involved in mRNA export termination) as identified by affinity-purification mass spectrometry; MKRN2 binds selectively to the 3' UTR of a diverse subset of mRNAs; morpholino knockdown or CRISPR/Cas9 knockout of MKRN2 partially rescues retinal developmental defects upon GLE1 depletion in zebrafish, establishing epistasis; knockdown of MKRN2 enhances nuclear export of MKRN2-associated mRNAs. |
Affinity purification–mass spectrometry, zebrafish morpholino knockdown, CRISPR/Cas9 knockout, genetic epistasis, ribonomic (RIP-seq) approaches |
Cell reports |
High |
32460013
|
| 2018 |
MKRN2 inhibits migration and invasion of non-small-cell lung cancer cells through downregulation of the PI3K/Akt pathway, as demonstrated by MKRN2 silencing and overexpression experiments in NSCLC cell lines. |
MKRN2 siRNA knockdown and overexpression, migration and invasion assays, Western blot for PI3K/Akt pathway components |
Journal of experimental & clinical cancer research |
Medium |
30103781
|
| 2022 |
MKRN2 promotes ubiquitination-mediated degradation of PKM2 (pyruvate kinase M2) and attenuates PKM2's effect on ERK signaling, thereby inhibiting gastric cancer cell proliferation. |
Co-IP, ubiquitination assay, overexpression and knockdown, CCK-8, in vivo xenograft |
Aging |
Medium |
35196650
|
| 2023 |
MKRN2 interacts with STAT1; Co-IP assays show a direct MKRN2–STAT1 interaction in testis and MEF cells, and STAT1 expression is significantly decreased in MKRN2 knockout testes. MKRN2 also regulates SIX4 and tenascin C (TNC) expression via EBF transcription factor 2 (EBF2). |
Mkrn2 knockout mouse model, Co-IP, Western blot, qRT-PCR |
Frontiers in endocrinology |
Medium |
36967804
|
| 2024 |
MKRN2 associates with influenza A virus (IAV) mRNA and positively regulates IAV mRNA nuclear-cytoplasmic trafficking, potentially through an association with the RNA export mediator GLE1; in the absence of MKRN2, IAV mRNAs accumulate in the nucleus and may be degraded by the nuclear RNA exosome complex. |
RNA interactome capture (RIC), MKRN2 knockdown, fluorescence microscopy for mRNA localization, functional viral replication assays |
PLoS pathogens |
Medium |
38753876
|
| 2025 |
MKRN2 selectively inhibits IL-6 translation (not transcription) in LPS-activated macrophages by binding Il6 mRNA and attaching K29-linked polyubiquitin chains to Lys179 of PAIP1 (a translation initiation coactivator), blocking PAIP1–eIF4A interaction and reducing translational efficiency of Il6 mRNA; LysM-Cre+Mkrn2fl/fl mice showed increased serum IL-6 after LPS and increased severity of experimental colitis. |
Conditional macrophage-specific Mkrn2 knockout, RNA-binding assays, ubiquitination assay with K29-linkage specificity, Co-IP for PAIP1–eIF4A interaction, polysome profiling, experimental colitis model |
Nature immunology |
High |
40524017
|
| 2024 |
MKRN2 is a substrate of lncCCKAR-5; lncCCKAR-5 acts as a scaffold facilitating interaction between MKRN2 and LMNA, promoting ubiquitin-mediated degradation of LMNA, with this effect augmented by N6-adenosine methylation of lncCCKAR-5. |
Co-IP, ubiquitination assay, lncRNA overexpression/knockdown, Western blot |
The Journal of investigative dermatology |
Medium |
38242315
|
| 2025 |
MKRN2 directly targets PPP2CA (Protein Phosphatase 2 Catalytic Subunit Alpha) for K48-linked ubiquitination at its K41 residue, leading to proteasomal degradation of PPP2CA; this results in increased β-catenin phosphorylation and decreased β-catenin protein levels, causing inactivation of Wnt signaling and apoptosis in clear cell renal cell carcinoma cells. |
Co-IP, immunofluorescence, K48-linkage-specific ubiquitination assay, site-directed mutagenesis (K41), in vivo xenograft |
International journal of biological sciences |
High |
40959281
|
| 2025 |
MKRN2 mediates ubiquitination of CSDE1 at four specific lysine residues (K81, K91, K208, K727); MKRN2 and CSDE1 co-localize in liquid-liquid phase separation (LLPS) condensates, and disruption of either protein impairs condensate formation; Mkrn2 knockout mice exhibit sex-specific social abnormalities resembling ASD; MARK1 and HNRNPUL2 mRNAs are identified as ubiquitination-dependent targets of CSDE1. |
Mass spectrometry substrate identification, lysine mutagenesis, LLPS assays in HEK293 and SH-SY5Y cells, Mkrn2 knockout mice, behavioral assays |
Frontiers in cellular neuroscience |
High |
41757349
|
| 2025 |
MKRN2 is recruited to stress granules (SGs) in a manner dependent on active ubiquitination (UBA1 activity); MKRN2 promotes SG formation and disassembly following stress recovery by preventing accumulation of defective ribosomal products (DRiPs) within SGs. |
Proximity proteomics (BioID), UBA1 inhibition, MKRN2 localization imaging, stress granule formation and dissolution assays |
bioRxivpreprint |
Medium |
bio_10.1101_2025.10.15.682570
|
| 2026 |
The covalent molecular glue DPB directly modifies Cys335 of MKRN2's E3 ligase domain and creates a neo-interface that recruits the ribosomal protein RPS7 to MKRN2, inducing ubiquitination and proteasomal degradation of RPS7, triggering nucleolar stress and apoptosis selectively in p53-deficient NSCLC cells; this synthetic lethal effect depends on a functional MKRN2–RPS7 axis. |
Quantitative thiol-reactivity proteomics (QTRP), biophysical assays, site-directed mutagenesis (Cys335), Co-IP-mass spectrometry, genetic KO/rescue, in vivo orthotopic mouse model |
British journal of pharmacology |
High |
41991154
|
| 2025 |
MKRN2 promotes ubiquitination-mediated degradation of p53 in lung epithelial cells; Co-IP confirms direct MKRN2–p53 interaction; MKRN2 overexpression reduces LPS-induced apoptosis and lung injury through p53 downregulation. |
Co-IP, ubiquitination assay, transcriptome sequencing, adenovirus-mediated overexpression, siRNA knockdown, in vivo LPS ARDS model |
Biochemical and biophysical research communications |
Medium |
40885043
|
| 2025 |
MKRN2 directly targets NF-κB p65 for proteasomal degradation via its E3 ubiquitin ligase activity, constraining NF-κB/COX2-mediated inflammatory signaling in the tumor microenvironment; MKRN2 deficiency promotes M1-to-M2 macrophage polarization switch and tumor growth acceleration in MKRN2 knockout mice. |
MKRN2 knockout mice, tumor implantation models, immune cell composition analysis (flow cytometry), Western blot for p65/COX2 |
Cancer letters |
Medium |
40925500
|
| 2026 |
MKRN2 promotes HCC cell proliferation through activation of the p38 MAPK signaling pathway; MKRN2 depletion arrests the cell cycle at G1/S and reduces c-Myc activation; RNA-seq analysis placed MKRN2 in cell cycle regulation and p38 MAPK signaling. |
MKRN2 knockdown, RNA-seq, flow cytometry, CCK-8/colony/EdU assays, in vivo xenograft |
Human cell |
Medium |
41741886
|