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

Ishiwata-Endo, H.; Kato, J.; Oda, H.; Sun, J.; Yu, Z.-X.; Liu, C.; Springer, D. A.; Dagur, P. K.; Lizak, M. J.; Murphy, E.; Moss, J.

doi:10.1101/2023.02.06.527366

bioRxiv · 10.1101/2023.02.06.527366

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

Ishiwata-Endo, H.·Kato, J.·Oda, H.·Sun, J.·Yu, Z.-X.·Liu, C.·Springer, D. A.·Dagur, P. K.·Lizak, M. J.·Murphy, E.·Moss, J.

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Abstract

Arginine-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 does Arh1 deficiency. In this study, Artc1-KO and Artc1/Arh1-double-KO mice showed decreased spontaneous tumorigenesis and increased age-dependent, multi-organ inflammation with upregulation of pro-inflammatory cytokine TNF-. In a xenograft model using tumorigenic Arh1-KO mouse embryonic fibroblasts (MEFs), tumorigenicity was decreased in Artc1-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 of Artc1-KO was less than their Artc1-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 O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/527366v1_ufig1.gif" ALT="Figure 1"> View larger version (84K): org.highwire.dtl.DTLVardef@1cded54org.highwire.dtl.DTLVardef@9851ceorg.highwire.dtl.DTLVardef@22cd8aorg.highwire.dtl.DTLVardef@e42e7a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ishiwata-Endo, H., Kato, J., Oda, H., Sun, J., Yu, Z.-X., Liu, C., Springer, D. A., Dagur, P. K., Lizak, M. J., Murphy, E., Moss, J.. 2023-02-06. Mono-ADP-ribosyltransferase 1 (Artc1)-deficiency decreases tumorigenesis, increases inflammation, decreases cardiac contractility, and reduces survival. https://doi.org/10.1101/2023.02.06.527366

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