Opposing effects of an F-box protein and the HSP90 chaperone network on microtubule stability and neurite growth in Caenorhabditis elegans

Development. 2020 Jun 17;147(12):dev189886. doi: 10.1242/dev.189886.


Molecular chaperones often work collaboratively with the ubiquitylation-proteasome system (UPS) to facilitate the degradation of misfolded proteins, which typically safeguards cellular differentiation and protects cells from stress. In this study, however, we report that the Hsp70/Hsp90 chaperone machinery and an F-box protein, MEC-15, have opposing effects on neuronal differentiation, and that the chaperones negatively regulate neuronal morphogenesis and functions. Using the touch receptor neurons (TRNs) of Caenorhabditis elegans, we find that mec-15(-) mutants display defects in microtubule formation, neurite growth, synaptic development and neuronal functions, and that these defects can be rescued by the loss of Hsp70/Hsp90 chaperones and co-chaperones. MEC-15 probably functions in a Skp-, Cullin- and F-box- containing complex to degrade DLK-1, which is an Hsp90 client protein stabilized by the chaperones. The abundance of DLK-1, and likely other Hsp90 substrates, is fine-tuned by the antagonism between MEC-15 and the chaperones; this antagonism regulates TRN development, as well as synaptic functions of GABAergic motor neurons. Therefore, a balance between the UPS and the chaperones tightly controls neuronal differentiation.

Keywords: Microtubules; Molecular chaperones; Neurite growth; Protein homeostasis; Touch receptor neurons; Ubiquitylation-proteasome system.

Publication types

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

MeSH terms

  • Animals
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • F-Box Proteins / antagonists & inhibitors
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • GABAergic Neurons / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Microtubules / metabolism*
  • Molecular Chaperones / antagonists & inhibitors
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Mutagenesis
  • Neurites / physiology*
  • Neurons, Afferent / metabolism
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability
  • RNA Interference
  • RNA, Double-Stranded
  • Ubiquitin / metabolism
  • Ubiquitination


  • Caenorhabditis elegans Proteins
  • F-Box Proteins
  • HSP90 Heat-Shock Proteins
  • Heat-Shock Proteins
  • MEC-15 protein, C elegans
  • Molecular Chaperones
  • RNA, Double-Stranded
  • STI-1 protein, C elegans
  • Ubiquitin
  • DLK-1 protein, C elegans
  • MAP Kinase Kinase Kinases
  • Proteasome Endopeptidase Complex