The Viral Defense Gene RNaseL Acts as a Regeneration Repressor

Abstract

Mammalian injury responses are characterized by fibrosis and scarring rather than functional regeneration. Limited regenerative capacity in mammals could reflect a loss of pro-regeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover programs governing regeneration in mammals, we performed comprehensive transcript screening in human subjects after laser rejuvenation treatment. We searched for overlapping transcripts also associated with Wound Induced Hair Neogenesis (WIHN), a rare example of regeneration in mice. We found the anti-viral endoribonuclease RNase L to be a powerful suppressor of regeneration. Rnasel-/- mice exhibit remarkable regenerative capacity and accelerated wound healing following injury, through the production of IL-36α. Consistent with the known role of RNase L to stimulate caspase-1 signaling, we find that pharmacologic inhibition of caspases promotes regeneration in a novel IL-36-dependent manner. We also find a gene set of inner root sheath keratins, such as KRT71, that is associated with poor wound healing in mouse and man, and decreases with caspase inhibition. Finally, these responses are not limited to skin, but occur following intestinal injury as well, suggesting that suppression of regeneration is a general characteristic of epithelial wound healing. In all, this work suggests that RNaseL functions as a regeneration repressor gene in a functional tradeoff that prioritizes host antiviral abilities and is a target to enhance healing in multiple epithelial organs, perhaps even during viral infection.