KAT2paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells

Abstract

ABSTRACTHistone acetyltransferasesKAT2AandKAT2Bare paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murineKat2genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and dsRIP-seq were employed to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling.Kat2aandKat2btherefore play an essential role in regulating mitochondrial functions as well as maintaining intestinal health.Highlights of the workKat2aandKat2bdouble knockout in the murine intestinal epithelium triggers activation of the interferon signaling pathwayKat2a/Kat2bknockout leads to intestinal stem cell loss and other mucosal phenotypes consistent with interferon activationHistone PTM mass spec profiling reveals the first in vivo study showing H3K9ac-specific loss withKat2aandKat2bdouble knockout, yet without correlation to interferon signaling pathway genesComprehensive proteomic analysis identifies non-histone acetyl-lysine targets of KAT2 in the mouse intestine in vivo, including mitochondrial proteinsMitochondrial function is compromised uponKat2lossdsRIP-seq identifies double-stranded RNA from the mitochondria as a trigger for the intrinsic immune response uponKat2double knockout