ArticleCell biology and toxicology2026
E3 ubiquitin ligase trim36 targets ddx3x for degradation to reprogram macrophage polarization and ameliorate tubal factor infertility in rats.
Article in Cell biology and toxicology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- E3 ubiquitin ligase SYVN1 mediates K63-linked ubiquitination of DDX3X to activate Macrophage NLRP3 Inflammasome.bioRxiv : the preprint server for biology · 2026Article
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Abstract
objectiveTubal factor infertility (TFI), a major cause of female infertility, lacks effective therapies and is closely associated with macrophage-mediated inflammation. Although DDX3X regulates macrophage polarization, its specific contribution to TFI pathogenesis remains unclear, and the potential involvement of E3 ubiquitin ligase-mediated regulation of DDX3X protein stability in this condition has not been reported. Therefore, our study planned to explore the regulation of DDX3X by the E3 ubiquitin ligase TRIM36 and how this axis influences macrophage polarization and TFI pathogenesis.
methodsThe GSE262037 dataset and the STRING platform were analyzed through bioinformatics approaches to identify TRIM36, an E3 ubiquitin ligase of DDX3X. A mixed bacterial inoculation method was employed to establish a TFI model of rats, and the animals were treated with TRIM36 overexpression (oe-TRIM36). Stimulation of LPS in the fallopian tube epithelial cells was applied to establish the in vitro TFI model, which was treated by the conditioned medium (CM) from rat bone marrow-derived macrophages (BMDM) with LPS, silence (si)/oe-DDX3X, and/or oe-TRIM36 treatment. Co-Immunoprecipitation (Co-IP) detection was employed to analyze the regulation of si/oe-TRIM36 on the ubiquitination of DDX3X protein.
resultsDDX3X expression was significantly upregulated in TFI rats and showed a positive correlation with M1 macrophage polarization. Silencing DDX3X in rat BMDM promoted M2 polarization while suppressing M1 polarization, and the CM derived from these macrophages alleviated LPS-induced damage in fallopian tube epithelial cells. Bioinformatics and Co-IP identified TRIM36 as an E3 ubiquitin ligase binding DDX3X, and TRIM36 overexpression promoted the K48-linked polyubiquitination and the proteasomal degradation of DDX3X. Similarly, TRIM36-mediated DDX3X downregulation shifted macrophage polarization towards the M2 phenotype in vitro and protected fallopian tube epithelial cells against LPS-induced damage. Importantly, in vivo oe-TRIM36 therapy downregulated DDX3X, increased M2 macrophages, reduced tubal inflammation, and significantly alleviated infertility phenotypes in TFI model rats.
conclusionThis study identifies TRIM36 as a novel E3 ligase that targets DDX3X for proteasomal degradation, thereby driving macrophage M2 polarization and ameliorating TFI. The TRIM36/DDX3X axis may provide a promising therapeutic target for TFI treatment.
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