F-box protein MEC-15 promotes microtubule stability and neurite growth by antagonizing the HSP90 chaperone network in Caenorhabditis elegans

• Published in: bioRxiv
• Main Authors: Zheng, Chaogu, Atlas, Emily, Lee, Ho Ming Terence, Jao, Susan Laura Javier, Nguyen, Ken C Q, Hall, David H, Chalfie, Martin
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.02.2020
• Subjects: Cell differentiation; Chaperones; F-box protein; Hsp70 protein; Hsp90 protein; Motor neurons; Mutants; Proteasomes; Protein folding; Proteins; Synaptogenesis; Ubiquitination; Worms; γ-Aminobutyric acid
• DOI: 10.1101/2020.02.13.944967

Molecular chaperones often work collaboratively with the ubiquitination-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 antagonizes the activity of F-box protein MEC-15 to negatively regulate neuronal differentiation. Using the touch receptor neurons (TRNs) of C. elegans, we find that mec-15(-) mutants display defects in MT formation, neurite growth, synaptic development, and neuronal functions, and these defects can be rescued by the loss of Hsp70/Hsp90 chaperones and cochaperones. MEC-15 likely functions in a SCF 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 are fine-tuned by the antagonism between MEC-15 and chaperones, which regulates TRN development and synaptic functions of GABAergic motor neurons. Therefore, a balance between UPS and chaperones tightly controls neuronal differentiation.