Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• Post-translational modifications, specifically neddylation, are crucial in regulating protein stability and function.
• Cullin proteins, targets of neddylation, play key roles in protein degradation pathways, including the regulation of hypoxia-inducible factor (HIF).
• Understanding the role of deneddylase-1 (DEN-1/SENP8) in inflammatory processes is essential for developing targeted therapies.

Purpose of the Study:

• To investigate the function of human deneddylase-1 (DEN-1) in inflammatory responses.
• To define the therapeutic potential of targeting neddylation in models of mucosal inflammation.
• To examine the contribution of DEN-1 to the stabilization of hypoxia-inducible factor (HIF).

Main Methods:

• Pharmacological inhibition of neddylation using MLN4924 in human epithelial cells.
• Gene knockdown of DEN-1 in human intestinal epithelial cells.
• In vivo studies using a murine model of dextran sulfate sodium (DSS)-induced colitis.

Main Results:

• MLN4924 treatment stabilized HIF-1α, increased HIF promoter activity (2.5-fold), and induced HIF-target genes (up to 5-fold) in human epithelial cells.
• DEN-1 knockdown enhanced epithelial barrier formation kinetics, reduced permeability, and improved barrier restitution (2 ± 0.5-fold).
• MLN4924 treatment significantly reduced disease severity in DSS-induced colitis, improving weight loss, colon length, and histologic scores.

Conclusions:

• DEN-1 acts as a regulator of cullin neddylation, fine-tuning inflammatory responses both in vitro and in vivo.
• Pharmacological inhibition of cullin neddylation represents a potential therapeutic strategy for mucosal inflammatory diseases.
• Stabilization of HIF through neddylation inhibition shows promise in managing inflammatory conditions.