Interactome analysis of Adenylyl cyclase-associated protein 1

The direct inflammatory action of proprotein convertase subtilisin/kexin type 9 (PCSK9) is examined in vitro in monocytes and endothelial cells, as well as via an in vivo atherosclerosis animal model. PCSK9 exacerbates atherosclerosis in low-density lipoprotein receptor (LDLR)-/- mice, indicating an inflammatory effect mediated independently of the LDLR pathway. Here we show that Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9, serving a crucial role in the pro-inflammatory cascade of PCSK9 by enabling the induction of cytokines, the activation of Toll-like receptor 4 (TLR4), and the upregulation of scavenger receptors. We also present spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) as pivotal mediators in the inflammatory cascade subsequent to PCSK9-CAP1 binding. In human peripheral blood mononuclear cells (PBMCs), serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. Notably, the CAP1-fragment crystallizable region (CAP1-Fc) shows superior efficacy in mitigating PCSK9-mediated inflammatory signal transduction when compared with the PCSK9 inhibitor, evolocumab.