KAT2 paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells.

Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 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 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. Kat2a and Kat2b therefore play an essential role in regulating mitochondrial functions as well as maintaining intestinal health. Kat2a and Kat2b double knockout in the murine intestinal epithelium triggers activation of the interferon signaling pathway Kat2a/Kat2b knockout leads to intestinal stem cell loss and other mucosal phenotypes consistent with interferon activation Histone PTM mass spec profiling reveals the first in vivo study showing H3K9ac-specific loss with Kat2a and Kat2b double knockout, yet without correlation to interferon signaling pathway genes Comprehensive proteomic analysis identifies non-histone acetyl-lysine targets of KAT2 in the mouse intestine in vivo, including mitochondrial proteins Mitochondrial function is compromised upon Kat2 loss dsRIP-seq identifies double-stranded RNA from the mitochondria as a trigger for the intrinsic immune response upon Kat2 double knockout.

Citation

Mai-Uyen Nguyen, Sarah Potgieter, Winston Huang, Julie Pfeffer, Sean Woo, Caifeng Zhao, Matthew Lawlor, Richard Yang, Angela Halstead, Sharon Dent, José B Sáenz, Haiyan Zheng, Zuo-Fei Yuan, Simone Sidoli, Christopher E Ellison, Michael Verzi. KAT2 paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells. bioRxiv : the preprint server for biology. 2023 Sep 05

PMID: 37732252

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