Protein competition switches the function of COP9 from self-renewal to differentiation

Nature. 2014 Oct 9;514(7521):233-6. doi: 10.1038/nature13562.

Abstract

The balance between stem cell self-renewal and differentiation is controlled by intrinsic factors and niche signals. In the Drosophila melanogaster ovary, some intrinsic factors promote germline stem cell (GSC) self-renewal, whereas others stimulate differentiation. However, it remains poorly understood how the balance between self-renewal and differentiation is controlled. Here we use D. melanogaster ovarian GSCs to demonstrate that the differentiation factor Bam controls the functional switch of the COP9 complex from self-renewal to differentiation via protein competition. The COP9 complex is composed of eight Csn subunits, Csn1-8, and removes Nedd8 modifications from target proteins. Genetic results indicated that the COP9 complex is required intrinsically for GSC self-renewal, whereas other Csn proteins, with the exception of Csn4, were also required for GSC progeny differentiation. Bam-mediated Csn4 sequestration from the COP9 complex via protein competition inactivated the self-renewing function of COP9 and allowed other Csn proteins to promote GSC differentiation. Therefore, this study reveals a protein-competition-based mechanism for controlling the balance between stem cell self-renewal and differentiation. Because numerous self-renewal factors are ubiquitously expressed throughout the stem cell lineage in various systems, protein competition may function as an important mechanism for controlling the self-renewal-to-differentiation switch.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Binding, Competitive*
  • COP9 Signalosome Complex
  • Cell Differentiation*
  • Cell Proliferation
  • DNA Helicases / metabolism
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / cytology*
  • Drosophila melanogaster / metabolism*
  • Female
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism*
  • NEDD8 Protein
  • Ovary / cytology
  • Peptide Hydrolases / chemistry*
  • Peptide Hydrolases / metabolism*
  • Protein Binding
  • Stem Cells / cytology*
  • Stem Cells / metabolism*
  • Ubiquitins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CSN4 protein, Drosophila
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • NEDD8 Protein
  • Nedd8 protein, Drosophila
  • Ubiquitins
  • bam protein, Drosophila
  • Peptide Hydrolases
  • CSN5 protein, Drosophila
  • COP9 Signalosome Complex
  • DNA Helicases
  • bgcn protein, Drosophila