elegans development in CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust

and proofing. formatted HTML, PDF, and XML versions will be made available after technical processing, editing, This PDF is the version of the article that was accepted for publication after peer review. Fully unrestricted use and redistribution provided that the original author and source are credited. permitting Creative Commons Attribution License This article is distributed under the terms of the elife.elifesciences.org at Sign up for alerts Stay current on the latest in life science and biomedical research from eLife. Abstract 15 Genetic redundancy and pleiotropism have limited the discovery of functions associated with miRNAs and 16 other regulatory mechanisms. To overcome this, we performed an enhancer screen for developmental defects 17 caused by compromising both global miRISC function and individual genes in C. elegans. Among 126 18 interactors with miRNAs, we surprisingly found the CED-3 caspase that has only been well studied for its role 19 in promoting apoptosis, mostly through protein activation. We provide evidence for a non-apoptotic function of 20 CED-3 caspase that regulates multiple developmental events through proteolytic inactivation. Specifically, LIN-21 14, LIN-28 and DISL-2 proteins are known miRNA targets, key regulators of developmental timing, and/or stem 22 cell pluripotency factors involved in miRNA processing. We show CED-3 cleaves these proteins in vitro. We 23 also show CED-3 down-regulates LIN-28 in vivo, possibly rendering it more susceptible to proteasomal 24 degradation. This mechanism may critically contribute to the robustness of gene expression dynamics 25 governing proper developmental control.