ArticleCell death and differentiation2017
SUMO-triggered ubiquitination of NR4A1 controls macrophage cell death.
Article in Cell death and differentiation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 57 citations in OpenAlex.
- Post-translational modifications in Neuroimmune cells during neuroinflammation: integrated regulatory networks and therapeutic opportunities.Biology direct · 2026Review
- Prenatal cadmium exposure and male infertility in mice: A multi-generational mechanistic study.Eco-Environment & Health · 2026Article
- METTL10-Mediated PIAS3 Methylation Links Purine Metabolism to Gastric Cancer Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- SENP1: A perspective from immune cells to disease (Review).Oncology reports · 2025Review
- Hypoxia-mediated SUMOylation of FADD exacerbates endothelial cell injury via the RIPK1-RIPK3-MLKL signaling axis.Cell death & disease · 2025Article
- Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice.Nature communications · 2025Article
- Unraveling the critical role of SUMOylation in the governing of tumor immunity.Frontiers in immunology · 2025Review
- Functional Changes Associated With the Subcellular Localization of the Nuclear Receptor NR4A1.Biochemistry research international · 2025Review
- Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model.The Journal of clinical investigation · 2024Article
- Epigenetic Regulation of Fungal Secondary Metabolism.Journal of fungi (Basel, Switzerland) · 2024Review
- SUMOylation of nuclear receptor Nor1/NR4A3 coordinates microtubule cytoskeletal dynamics and stability in neuronal cells.Cell & bioscience · 2024Article
- Identification of SUMOylation-related biomarkers in papillary thyroid carcinoma.Cancer cell international · 2024Article
- Hypoxia and low-glucose environments co-induced HGDILnc1 promote glycolysis and angiogenesis.Cell death discovery · 2024Article
- TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence.Nature communications · 2024Article
- Caspase 6/NR4A1/SOX9 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed fatty liver.Cell death discovery · 2023Article
- UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer.The Journal of clinical investigation · 2023Article
- Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation.International journal of molecular sciences · 2022Article
- Fine-tuning of SUMOylation modulates drought tolerance of apple.Plant biotechnology journal · 2022Article
- Deletion of pleiotrophin impairs glucose tolerance and liver metabolism in pregnant mice: Moonlighting role of glycerol kinase.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- The SUMOylation of TAB2 mediated by TRIM60 inhibits MAPK/NF-κB activation and the innate immune response.Cellular & molecular immunology · 2021Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nuclear receptor NR4A1 has been implicated as a key regulator in a wide range of pathophysiological responses. As an immediate early response gene, NR4A1 can be rapidly and potently induced by a variety of stimuli. Its induction is followed by its rapid degradation, but the mechanism by which NR4A1 is degraded remains poorly understood. Here we show that nuclear receptor NR4A1 is sumoylated by SUMO2/3. Upon poly-SUMO modification, NR4A1 can be targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. The SUMO E3 ligase PIAS3 promotes SUMOylation and polyubiquitination of NR4A1, while the SUMO protease SENP1 acts to de-conjugate SUMO. We demonstrate that this pathway is important for rapid degradation of NR4A1 after induced by stress. Moreover, we identify two SUMO modification sites in NR4A1 that are critical for maintaining low levels of NR4A1 expression. Mutation of these two NR4A1 SUMO modification sites enhances the stability of NR4A1. Importantly, we show that SUMOylation is critical in controlling NR4A1 function in inflammatory cytokine signaling and controlling macrophage cell death. SUMOylation and subsequent ubiquitination on NR4A1 mitigates its inhibition of innate immune signaling, such as TNF-α- and IL-1β-induced NF-κB activation. This mechanism of sequential SUMOylation and ubiquitination, which together control the degradation of NR4A1, could be exploited for the therapeutic treatment of diseases with NR4A1 involvement.
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