Protein kinase a regulates cyclooxygenase-2 expression through the RNA-binding proteins HuR and TTP

Cyclooxygenase-2 (COX-2/PTGS2) is an inducible enzyme central to inflammatory responses, and its expression is tightly regulated. Elevated intracellular cAMP levels are known to stimulate COX-2 expression. However, the precise mechanism by which protein kinase A (PKA), the primary cAMP effector, mediates this process remains elusive. In this study, we investigated the role of PKA in regulating COX-2 expression in macrophages. We found that PKA activity is essential for COX-2 expression, primarily through a posttranscriptional mechanism that enhances COX-2 mRNA stability. This effect is mediated by the interaction between PKA and the RNA-binding proteins HuR (ELAVL1) and TTP (tristetraprolin/ZFP36). Specifically, we observed that the catalytic subunit of PKA directly interacts with HuR, Hu antigen R (HuR), a well-established COX-2 mRNA stabilizer. PKA activation increased HuR binding to COX-2 mRNA, and pharmacological inhibition of HuR abrogated COX-2 expression in macrophages stimulated with PGE₂ and interleukin-1β. Furthermore, PKA stimulates the phosphorylation of TTP, an mRNA-destabilizing protein, thereby reducing its binding to the COX-2 transcript. We propose that PKA enhances COX-2 expression by interacting with HuR, maintaining proximity to COX-2 mRNA, and protecting it from TTP-mediated destabilization. Our findings reveal a mechanistic link between PKA activity and COX-2 mRNA stability through HuR and TTP, highlighting the role of RNA-binding proteins as novel effectors of PKA signaling in posttranscriptional regulation.