Identification of a CCDC92-mediated non-canonical STAT1 signaling cascade in endothelial cells inhibiting initiation of atherosclerosis

Coronary artery disease (CAD) affects 315 million individuals globally. A recent genome-wide association study linked rs9863, a SNP in the 3’-UTR of CCDC92 , to risk of CAD, but their causal relationship remains unclear. In this study, we demonstrated that downregulation of endothelial CCDC92 is causal to atherosclerotic CAD. CCDC92 expression was significantly downregulated in vascular endothelium from human CAD patients and atherosclerotic ApoE −/− mice. GTEx analysis revealed significant association between downregulation and alternative splicing of CCDC92 and rs9863 risk allele T (eQTL) via miR-377-3p. CCDC92 knockdown inhibited the proliferation, migration, and capillary tube formation of coronary artery endothelial cells (CAECs) and enhanced monocyte adhesion to and transmigration across CAECs monolayers involved in the initiation of atherosclerosis. Mechanistically, CCDC92 knockdown increased the expression of total and phosphorylated STAT1 independent of JAK or SRC activation. CCDC92 interacted with STAT1 and anchored it to the 19 S proteasome via ADRM1/UCHL5 for degradation. CCDC92 knockdown attenuated the complex formation between STAT1 and ADRM1/UCHL5, inhibited STAT1 degradation, and consequently increased STAT1 expression. CCDC92 overexpression did not affect the function of CAECs. CCDC92 knockdown upregulated endothelial activation markers ICAM1 and VCAM1 by activating NFκB. In vivo endothelial knockdown of Ccdc92 with lentiviral-shCcdc92 in atherosclerotic ApoE −/− mice aggravated lesion formation by triggering endothelial activation, activating STAT1, and upregulating STAT1-target genes. Collectively, we define a novel noncanonical STAT1 inhibitory pathway in endothelial cells, in which CCDC92 acts as an adaptor that anchors STAT1 to the 19 S proteasome through ADRM1/UCHL5, and link the CCDC92-STAT1 pathway to atherosclerosis.