The serine protease DPP9 and the redox sensor KEAP1 form a mutually inhibitory complex.

Area of Science:

• Immunology
• Cellular Biology
• Biochemistry

Background:

• Synthetic DPP9 inhibitors activate NLRP1 and CARD8 inflammasomes, suggesting endogenous regulators exist.
• The physiological mechanisms controlling DPP9 activity remain largely unknown.

Purpose of the Study:

• To identify and characterize DPP9-binding proteins.
• To uncover endogenous mechanisms regulating DPP9 activity and inflammasome activation.

Main Methods:

• Protein-protein interaction studies to identify DPP9-binding partners.
• Biochemical assays to characterize the functional consequences of these interactions.
• Investigated the role of cellular redox state in regulating DPP9 conformation and activity.

Main Results:

• Identified KEAP1 as a DPP9-binding protein that stabilizes an inactive DPP9 conformation.
• Demonstrated that inactive DPP9 inhibits KEAP1-mediated NRF2 degradation, inducing an antioxidant response.
• Established that DPP9 activity is coupled to the intracellular redox potential.

Conclusions:

• An endogenous mechanism for DPP9 inhibition involving KEAP1 and cellular redox state has been discovered.
• This finding provides a foundation for understanding DPP9 regulation and its role in innate immunity.
• Further research can explore additional biomolecules regulating DPP9, its interaction with KEAP1, and inflammasome pathways.