TY - JOUR
T1 - Opposing effects of an F-box protein and the HSP90 chaperone network on microtubule stability and neurite growth in Caenorhabditis elegans
AU - Zheng, Chaogu
AU - Atlas, Emily
AU - Lee, Ho Ming Terence
AU - Jao, Susan Laura Javier
AU - Nguyen, Ken C.Q.
AU - Hall, David H.
AU - Chalfie, Martin
N1 - Publisher Copyright:
© 2020. Published by The Company of Biologists Ltd
PY - 2020/6/17
Y1 - 2020/6/17
N2 - 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.
AB - 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.
KW - Microtubules
KW - Molecular chaperones
KW - Neurite growth
KW - Protein homeostasis
KW - Touch receptor neurons
KW - Ubiquitylation-proteasome system
UR - http://www.scopus.com/inward/record.url?scp=85086746522&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086746522&partnerID=8YFLogxK
U2 - 10.1242/dev.189886
DO - 10.1242/dev.189886
M3 - Article
C2 - 32467239
AN - SCOPUS:85086746522
SN - 0950-1991
VL - 147
JO - Development (Cambridge)
JF - Development (Cambridge)
IS - 12
M1 - dev189886
ER -