title: CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust development in C. elegans.
abstract: Genetic redundancy and pleiotropism have limited the discovery of functions associated with miRNAs and other regulatory mechanisms. To overcome this, we performed an enhancer screen for developmental defects caused by compromising both global miRISC function and individual genes in Caenorhabditis elegans. Among 126 interactors with miRNAs, we surprisingly found the CED-3 caspase that has only been well studied for its role in promoting apoptosis, mostly through protein activation. We provide evidence for a non-apoptotic function of CED-3 caspase that regulates multiple developmental events through proteolytic inactivation. Specifically, LIN-14, LIN-28, and DISL-2 proteins are known miRNA targets, key regulators of developmental timing, and/or stem cell pluripotency factors involved in miRNA processing. We show CED-3 cleaves these proteins in vitro. We also show CED-3 down-regulates LIN-28 in vivo, possibly rendering it more susceptible to proteasomal degradation. This mechanism may critically contribute to the robustness of gene expression dynamics governing proper developmental control.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Weaver
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Zabinsky
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, United States.
authors.forename: Yi M
authors.initials: YM
authors.lastname: Weaver
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.
authors.forename: Eui Seung
authors.initials: ES
authors.lastname: Lee
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.
authors.forename: Ding
authors.initials: D
authors.lastname: Xue
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Han
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000166:cytology / Q000196:embryology* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D058685:Genetic Pleiotropy; D016678:Genome; D006801:Humans; D007814:Larva / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism; D034622:RNA Interference; D034743:RNA-Induced Silencing Complex; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors
chemical_list: D029742:Caenorhabditis elegans Proteins; D035683:MicroRNAs; D034743:RNA-Induced Silencing Complex; D020169:Caspases; C089223:ced-3 protein, C elegans
keywords: C. elegans; DIS3L2; GW182; LIN28; caspase; developmental biology; heterochronic; miRNA; stem cells