| 2017 |
MKRN2 is a ubiquitin E3 ligase that binds to the p65 subunit of NF-κB, promotes its polyubiquitination and proteasome-dependent degradation through the MKRN2 RING finger domain, thereby suppressing p65-mediated NF-κB transactivation. MKRN2 and PDLIM2 synergistically promote polyubiquitination and degradation of p65. MKRN2 was identified via yeast two-hybrid screening as a PDLIM2-interacting protein. Knockdown of MKRN2 in dendritic cells resulted in increased nuclear p65 and augmented proinflammatory cytokine production. |
Yeast two-hybrid screening, co-immunoprecipitation, in vitro ubiquitination assay, RING domain mutagenesis, siRNA knockdown, NF-κB reporter assay |
Scientific reports |
High |
28378844
|
| 2018 |
MKRN2 inhibits migration and invasion of non-small-cell lung cancer cells through downregulation of the PI3K/Akt pathway, as demonstrated by altered MKRN2 expression in NSCLC cell lines. |
siRNA knockdown and overexpression in NSCLC cell lines, migration/invasion assays, western blotting for PI3K/Akt pathway components |
Journal of experimental & clinical cancer research : CR |
Medium |
30103781
|
| 2020 |
MKRN2 ubiquitinates IGF2BP3 (an RNA-binding protein) as a direct substrate, leading to its degradation. This MKRN2-mediated ubiquitination of IGF2BP3 regulates the expression of CD44 and PDPN (downstream IGF2BP3 targets) in neuroblastoma SHSY5Y cells. MKRN2 knockdown promotes proliferation and migration of these cells. |
shRNA knockdown, co-immunoprecipitation, in vitro ubiquitination assay, western blotting |
Biochemical and biophysical research communications |
Medium |
32560817
|
| 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. Loss of Mkrn2 results in decreased expression of Odf2, a protein vital for spermatogenesis. |
Knockout mouse model, histology, sperm analysis, western blotting for Odf2 expression |
Scientific reports |
Medium |
28008940
|
| 2020 |
Mkrn2 deficiency leads to abnormally high apoptosis in testes. MKRN2 inhibits expression of p53 apoptosis effector PERP, and loss of Mkrn2 upregulates PERP, implicating a Mkrn2-p53/PERP signaling axis in protecting germ cells from excessive apoptosis during spermatogenesis. |
Mkrn2 knockout mouse model, digital gene expression profiling, GSEA/KEGG pathway analysis, protein expression analysis |
Asian journal of andrology |
Low |
31489847
|
| 2020 |
MKRN2 directly interacts with and ubiquitinates p53, promoting its degradation, thereby promoting melanoma cell proliferation in a p53-dependent manner. Downregulation of MKRN2 inhibited melanoma cell growth specifically in cells with functional p53 (rescued in p53-knockout cells). |
Co-immunoprecipitation, GST pulldown, in vitro ubiquitination assay, CRISPR-Cas9 p53 knockout, MTT and colony formation assays, shRNA knockdown |
Oncology letters |
High |
32194692
|
| 2020 |
MKRN2 physically interacts with GLE1 (a DEAD-box helicase activator implicated in mRNA export termination), as identified by affinity-purification mass spectrometry. MKRN2 binds selectively to the 3' UTR of a subset of mRNAs, and nuclear export of MKRN2-associated mRNAs is enhanced upon MKRN2 knockdown. Genetic epistasis in zebrafish shows that morpholino knockdown or CRISPR knockout of MKRN2 partially rescues retinal developmental defects caused by GLE1 depletion, placing MKRN2 downstream of GLE1 in mRNA export regulation. |
Affinity-purification mass spectrometry, ribonomic approaches (RNA-binding profiling), morpholino knockdown, CRISPR/Cas9 knockout in zebrafish, genetic epistasis |
Cell reports |
High |
32460013
|
| 2024 |
MKRN2 associates with influenza A virus (IAV) mRNAs and positively regulates IAV mRNA nuclear-cytoplasmic trafficking, potentially through an association with GLE1. In the absence of MKRN2, IAV mRNAs accumulate in the nucleus of infected cells and may be degraded by the nuclear RNA exosome. |
RNA interactome capture (RIC), MKRN2 knockdown, RNA FISH, nuclear/cytoplasmic fractionation |
PLoS pathogens |
Medium |
38753876
|
| 2025 |
MKRN2 selectively inhibits IL-6 expression in LPS-activated macrophages. Mechanistically, after binding to Il6 mRNA, MKRN2 attaches K29 polyubiquitin chains to the Lys179 residue of PAIP1 (a translation initiation coactivator), which blocks the PAIP1-eIF4A interaction and inhibits translational efficiency of Il6 mRNA. LysM-Cre+Mkrn2fl/fl mice showed increased serum IL-6 after LPS and increased severity of experimental colitis. |
Conditional knockout mouse model, in vitro ubiquitination assay, mutagenesis of PAIP1 K179, Co-immunoprecipitation, polysome profiling, RNA-binding assay |
Nature immunology |
High |
40524017
|
| 2022 |
MKRN2 promotes ubiquitination-mediated degradation of PKM2 and attenuates its effect on ERK, thereby inhibiting gastric cancer cell proliferation. |
Overexpression and knockdown in gastric cancer cell lines, co-immunoprecipitation, ubiquitination assay, western blotting for ERK pathway, in vivo xenograft |
Aging |
Medium |
35196650
|
| 2023 |
MKRN2 directly interacts with STAT1 in testis and MEF cells, as shown by Co-IP. MKRN2 also regulates expression of SIX4 and TNC via EBF2 transcription factor in mice. Loss of Mkrn2 in knockout mice results in decreased STAT1, SIX4, and TNC expression and male infertility. |
Mkrn2 knockout mouse model, co-immunoprecipitation, western blotting, transcriptional analysis |
Frontiers in endocrinology |
Low |
36967804
|
| 2025 |
MKRN2 interacts with PPP2CA (Protein Phosphatase 2 Catalytic Subunit Alpha) and promotes K48-linked ubiquitination at its K41 residue, leading to proteasomal degradation of PPP2CA. This results in increased β-catenin phosphorylation and decreased β-catenin levels, causing inactivation of the Wnt signaling pathway and increased apoptosis in clear cell renal cell carcinoma cells. |
Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay with K48-linkage specificity, western blotting for β-catenin and Wnt pathway, in vivo xenograft |
International journal of biological sciences |
Medium |
40959281
|
| 2025 |
MKRN2 functions as an E3 ubiquitin ligase that targets NF-κB p65 for proteasomal degradation, constraining NF-κB/COX2-mediated inflammatory signaling. MKRN2 deficiency promotes M1-to-M2 macrophage polarization in tumor-associated macrophages, leading to accelerated tumor growth in MKRN2 knockout mice. |
MKRN2 knockout mouse model, in vivo tumor implantation, flow cytometry for macrophage phenotyping, reconstitution experiments with MKRN2 overexpression |
Cancer letters |
Medium |
40925500
|
| 2025 |
MKRN2 promotes ubiquitination and proteasomal degradation of p53 in lung epithelial cells, attenuating LPS-induced apoptosis. Co-IP confirmed the direct interaction between MKRN2 and p53, and transcriptome sequencing confirmed MKRN2 modulates apoptosis via the p53 signaling pathway. |
Co-immunoprecipitation, in vitro ubiquitination assay, transcriptome sequencing, adenovirus-mediated overexpression, siRNA knockdown, in vivo LPS-ARDS mouse model |
Biochemical and biophysical research communications |
Medium |
40885043
|
| 2026 |
The covalent compound DPB directly targets MKRN2 by covalently modifying the Cys335 residue, acting as a molecular glue that recruits the ribosomal protein RPS7 to MKRN2. This induces ubiquitination and proteasomal degradation of RPS7, triggering nucleolar stress and apoptosis selectively in p53-deficient NSCLC cells. The synthetic lethal effect is entirely dependent on the MKRN2-RPS7 axis. |
Quantitative thiol-reactivity proteomics (QTRP), co-immunoprecipitation mass spectrometry, site-directed mutagenesis of Cys335, genetic knockout/rescue studies, biophysical binding assays, in vivo orthotopic mouse model |
British journal of pharmacology |
High |
41991154
|
| 2026 |
MKRN2 mediates ubiquitination of the RNA-binding protein CSDE1 at four specific lysine residues (K81, K91, K208, K727), identified by mass spectrometry and validated by mutagenesis. MKRN2 and CSDE1 form co-localized condensates via liquid-liquid phase separation (LLPS), which is disrupted by functional impairment of either protein. Mkrn2 knockout mice exhibit sex-specific social abnormalities recapitulating ASD features, and CSDE1-dependent targets MARK1 and HNRNPUL2 mRNAs are regulated in a ubiquitination-dependent manner. |
Mass spectrometry substrate identification, mutagenesis of CSDE1 lysine residues, LLPS assays in HEK293 and SH-SY5Y cells, Mkrn2 knockout mouse behavioral testing, western blotting |
Frontiers in cellular neuroscience |
Medium |
41757349
|
| 2025 |
MKRN2 localizes to stress granules (SGs) in a manner dependent on active ubiquitination (UBA1 activity). Within SGs, MKRN2 promotes proper SG formation and disassembly following stress recovery by preventing accumulation of defective ribosomal products (DRiPs). MKRN2 was identified as a SG-associated E3 ligase by proximity proteomics. |
Proximity proteomics (BioID), UBA1 inhibitor treatment, live-cell imaging of SG dynamics, loss-of-function assays |
bioRxivpreprint |
Medium |
bio_10.1101_2025.10.15.682570
|
| 2026 |
MKRN2 promotes cell cycle progression and proliferation of hepatocellular carcinoma cells through activation of the p38 MAPK signaling pathway, leading to c-Myc activation. MKRN2 depletion arrests cells at the G1/S transition. |
siRNA knockdown, RNA-seq, flow cytometry cell cycle analysis, western blotting for p38 MAPK and c-Myc, CCK-8/EdU/colony formation assays, in vivo xenograft |
Human cell |
Low |
41741886
|