Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response

Area of Science:

• Molecular Biology
• Immunology
• Cell Biology

Background:

• Regnase-1 (ZC3H12A) is an endoribonuclease that degrades mRNA for inflammation-related genes.
• Post-translational modifications, like phosphorylation, regulate Regnase-1 activity, but their specific roles are unclear.
• Interleukin-17 (IL-17) is a key cytokine in inflammatory diseases.

Purpose of the Study:

• To investigate the role of Regnase-1 phosphorylation in IL-17-mediated inflammation.
• To elucidate the molecular mechanism by which IL-17 affects Regnase-1 activity.
• To assess the therapeutic potential of blocking Regnase-1 phosphorylation in IL-17-driven diseases.

Main Methods:

• Utilized CRISPR/Cas-9 technology to generate Regnase-1 phosphorylation-deficient mutant mice.
• Investigated IL-17-induced Regnase-1 phosphorylation in vitro and in vivo.
• Assessed inflammatory responses in wild-type and mutant mice exposed to T helper 17 (Th17) cells.

Main Results:

• IL-17 induces phosphorylation of Regnase-1 in a nonhematopoietic cell-specific, Act1-TBK1/IKKi-dependent manner.
• Phosphorylated Regnase-1 is released from the ER to the cytosol, losing its mRNA degradation function.
• Regnase-1 phosphorylation-deficient mutant mice exhibited resistance to IL-17-mediated inflammation.
• IL-17 target gene expression was increased in the absence of functional Regnase-1 mRNA degradation.

Conclusions:

• Regnase-1 phosphorylation is a critical mechanism in IL-17-driven inflammation.
• The Act1-TBK1-IKKi signaling pathway mediates IL-17-induced Regnase-1 inactivation.
• Targeting Regnase-1 phosphorylation sites offers a potential therapeutic strategy for Th17-associated inflammatory diseases.