Mono-ADP-ribosyltransferase 1 (Artc1)-deficiency decreases tumorigenesis, increases inflammation, decreases cardiac contractility, and reduces survival

Abstract

AbstractArginine-specific mono-ADP-ribosylation is a reversible post-translational modification; arginine-specific, cholera toxin-like mono-ADP-ribosyltransferases (ARTCs) transfer ADP-ribose from NAD+to arginine, followed by cleavage of ADP-ribose-(arginine)protein bond by ADP-ribosylarginine hydrolase 1 (ARH1), generating unmodified (arginine)protein. ARTC1 has been shown to enhance tumorigenicity as doesArh1deficiency. In this study,Artc1-KO andArtc1/Arh1-double-KO mice showed decreased spontaneous tumorigenesis and increased age-dependent, multi-organ inflammation with upregulation of pro-inflammatory cytokine TNF-α. In a xenograft model using tumorigenicArh1-KO mouse embryonic fibroblasts (MEFs), tumorigenicity was decreased inArtc1-KO and heterozygous recipient mice, with tumor infiltration by CD8+T cells and macrophages, leading to necroptosis, suggesting that ARTC1 promotes the tumor microenvironment. Furthermore,Artc1/Arh1-double-KO MEFs showed decreased tumorigenesis in nude mice, showing that tumor cells as well as tumor microenvironment require ARTC1. By echocardiography and MRI,Artc1-KO and heterozygous mice showed male-specific, reduced myocardial contractility. Furthermore,Artc1-KO male hearts exhibited enhanced susceptibility to myocardial ischemia-reperfusion-induced injury with increased receptor-interacting protein kinase 3 (RIP3) protein levels compared to WT mice, suggesting that ARTC1 suppresses necroptosis. Overall survival rate ofArtc1-KO was less than theirArtc1-WT counterparts, primarily due to enhanced immune response and inflammation. Thus, anti-ARTC1 agents may reduce tumorigenesis but may increase multi-organ inflammation and decrease cardiac contractility.Graphical Abstract