A 3'UTR polymorphism disrupts IRF2BP2 autoregulation through an eIF4H translational enhancer

Area of Science:

• Molecular Biology
• Genetics
• Immunology

Background:

• Interferon regulatory factor 2 binding protein 2 (IRF2BP2) plays a role in suppressing interferon responses and inflammation.
• A specific 9-nucleotide deletion in the 3'UTR of IRF2BP2 (rs3045215) is associated with reduced protein expression and increased risk of coronary atherosclerosis and calcification.

Purpose of the Study:

• To investigate the molecular mechanism by which the IRF2BP2 3'UTR deletion variant affects protein expression and translation.
• To elucidate the role of eukaryotic initiation factor 4H (eIF4H) in IRF2BP2 autoregulation.

Main Methods:

• RNAfold analysis to predict RNA structures.
• siRNA knockdown of eIF4H.
• Luciferase reporter assays with wild-type and deletion-variant IRF2BP2 3'UTRs.
• RNA gel mobility shift assays using macrophage extracts.

Main Results:

• The 9-nucleotide deletion disrupts an RNA stem-loop structure necessary for eIF4H recruitment and translation enhancement.
• siRNA knockdown of eIF4H reduced endogenous IRF2BP2 protein levels and impaired reporter gene translation.
• The deletion variant prevented IRF2BP2 protein from interacting with its own 3'UTR RNA.

Conclusions:

• The rs3045215 deletion variant abolishes IRF2BP2 autoregulation by disrupting an eIF4H-dependent translational enhancer.
• This mechanism contributes to lower IRF2BP2 protein levels and increased cardiovascular disease risk.