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

Elife. 2014 Dec 30;3:e04265. doi: 10.7554/eLife.04265.

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.

Keywords: C. elegans; DIS3L2; GW182; LIN28; caspase; developmental biology; heterochronic; miRNA; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / genetics*
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / embryology*
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Lineage / genetics
  • Embryonic Development / genetics*
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation, Developmental*
  • Genetic Pleiotropy
  • Genome
  • Humans
  • Larva / metabolism
  • MicroRNAs / metabolism*
  • Models, Biological
  • Molecular Sequence Data
  • Phenotype
  • Pluripotent Stem Cells / metabolism
  • RNA Interference
  • RNA-Induced Silencing Complex
  • Signal Transduction / genetics
  • Time Factors

Substances

  • Caenorhabditis elegans Proteins
  • MicroRNAs
  • RNA-Induced Silencing Complex
  • Caspases
  • ced-3 protein, C elegans