Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic Development

Dev Cell. 2017 Jun 19;41(6):665-673.e6. doi: 10.1016/j.devcel.2017.05.013. Epub 2017 Jun 8.

Abstract

Recent findings suggest that components of the classical cell death machinery also have important non-cell-death (non-apoptotic) functions in flies, nematodes, and mammals. However, the mechanisms for non-canonical caspase substrate recognition and proteolysis, and the direct roles for caspases in gene expression regulation, remain largely unclear. Here we report that CED-3 caspase and the Arg/N-end rule pathway cooperate to inactivate the LIN-28 pluripotency factor in seam cells, a stem-like cell type in Caenorhabditis elegans, thereby ensuring proper temporal cell fate patterning. Importantly, the caspase and the E3 ligase execute this function in a non-additive manner. We show that CED-3 caspase and the E3 ubiquitin ligase UBR-1 form a complex that couples their in vivo activities, allowing for recognition and rapid degradation of LIN-28 and thus facilitating a switch in developmental programs. The interdependence of these proteolytic activities provides a paradigm for non-apoptotic caspase-mediated protein inactivation.

Keywords: Arg/N-end rule; Lin28; UBR; developmental timing; heterochronic; non-apoptotic; proteasome; proteostasis; stem cell.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Caenorhabditis elegans / embryology
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / metabolism*
  • Caspases / metabolism*
  • Cell Differentiation / physiology*
  • Embryonic Development / genetics*
  • Gene Expression Regulation, Developmental / physiology*
  • Proteolysis
  • RNA-Binding Proteins / metabolism*
  • Signal Transduction / physiology
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • LIN-28 protein, human
  • RNA-Binding Proteins
  • Ubiquitin-Protein Ligases
  • Caspases
  • ced-3 protein, C elegans