ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2015
Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 70 citations in OpenAlex.
- Neddylation as a molecular integrator of metabolic dysfunction and endothelial dysfunction in type 2 diabetes.Acta pharmacologica Sinica · 2026Review
- Neddylation: from regulatory mechanisms to clinical implications in cancer.Journal of advanced research · 2026Review
- UBE2M deficiency in alveolar macrophages promotes emphysema through HIF-2α/MMP12 axis.Chinese medical journal pulmonary and critical care medicine · 2026Article
- Metabolic host-microbe crosstalk in stabilization of epithelial HIF.Microbiome · 2026Article
- Neddylation Targets and Stabilizes NLRP3 to Augment Inflammasome-Mediated Colitis and Mood Disorder.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- NEDD8, stress granules, and amyotrophic lateral sclerosis: unveiling the therapeutic potential of the NEDP1 protease.Essays in biochemistry · 2025Review
- NEDDylation Regulates CD8+ T-cell Metabolism and Antitumor Immunity.Cancer immunology research · 2025Article
- Review
- Identification of novel proteins in inflammatory bowel disease based on the gut-brain axis: a multi-omics integrated analysis.Clinical proteomics · 2024Article
- The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway.Biomolecules · 2024Review
- The implication of serum HLA-G in angiogenesis of multiple myeloma.Molecular medicine (Cambridge, Mass.) · 2024Article
- Article
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Review
- Authentication and validation of key genes in the treatment of atopic dermatitis with Runfuzhiyang powder: combined RNA-seq, bioinformatics analysis, and experimental research.Frontiers in genetics · 2024Article
- Mimicry of microbially-derived butyrate reveals templates for potent intestinal epithelial HIF stabilizers.Gut microbes · 2023Article
- Targeting neddylation as a novel approach to lung cancer treatment (Review).International journal of oncology · 2023Review
- Neddylation is required for perinatal cardiac development through stimulation of metabolic maturation.Cell reports · 2023Article
- Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways.International journal of molecular sciences · 2023Review
- Advances in the potential roles of Cullin-RING ligases in regulating autoimmune diseases.Frontiers in immunology · 2023Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
There is interest in understanding post-translational modifications of proteins in inflammatory disease. Neddylation is the conjugation of the molecule neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) to promote protein stabilization. Cullins are a family of NEDD8 targets important in the stabilization and degradation of proteins, such as hypoxia-inducible factor (HIF; via Cullin-2). Here, we elucidate the role of human deneddylase-1 (DEN-1, also called SENP8) in inflammatory responses in vitro and in vivo and define conditions for targeting neddylation in models of mucosal inflammation. HIF provides protection in inflammatory models, so we examined the contribution of DEN-1 to HIF stabilization. Pharmacologic targeting of neddylation activity with MLN4924 (IC50, 4.7 nM) stabilized HIF-1α, activated HIF promoter activity by 2.5-fold, and induced HIF-target genes in human epithelial cells up to 5-fold. Knockdown of DEN-1 in human intestinal epithelial cells resulted in increased kinetics in barrier formation, decreased permeability, and enhanced barrier restitution by 2 ± 0.5-fold. Parallel studies in vivo revealed that MLN4924 abrogated disease severity in murine dextran sulfate sodium colitis, including weight loss, colon length, and histologic severity. We conclude that DEN-1 is a regulator of cullin neddylation and fine-tunes the inflammatory response in vitro and in vivo. Pharmacologic inhibition of cullin neddylation may provide a therapeutic opportunity in mucosal inflammatory disease.
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