Proprotein convertase subtilisin/kexin type 9 inhibits interferon β expression through interacting with ATF-2.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid metabolism. A mutual interplay of lipid homeostasis and innate immune system has been increasingly recognized. We, therefore, studied the effect of PCSK9 on interferon (IFN) β expression. We show that PCSK9 decreases IFNβ promoter/enhancer activity, mRNA and protein levels, and its downstream 2',5'-oligoadenylate synthetase-1 mRNA level. ProPCSK9, but not the cleaved PCSK9, down-regulates IFNβ promoter/enhancer activity. Moreover, PCSK9 decreases IFNβ promoter/enhancer activity through the positive regulatory domain IV region where the activating transcription factor-2 (ATF-2)/c-Jun heterodimer binds. Mechanistically, we demonstrate an interaction between PCSK9 and ATF-2, which reduces ATF-2/c-Jun dimerization and ATF-2/c-Jun binding to the IFNβ enhancer. This novel function of PCSK9 should have important implications in optimizing the clinical use of PCSK9 inhibitors.