KAT2A and KAT2B prevent double-stranded RNA accumulation and interferon signaling to maintain intestinal stem cell renewal.

Abstract

Histone acetyltransferases <i>KAT2A</i> and <i>KAT2B</i> are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine <i>Kat2</i> genes 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 sequencing of immunoprecipitated double-stranded RNA were used to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling. <i>Kat2a</i> and <i>Kat2b</i> therefore play an essential role in regulating mitochondrial functions and maintaining intestinal health.