Protein quality control is vital to cellular function. The heat shock proteins (Hsps) are molecular chaperones that regulate various stages in the protein life cycle (including enhancing stability), whereas the ubiquitylation-proteasome system (UPS) targets proteins for degradation. The two pathways collaborate in certain contexts, but their relationship in normal development remains poorly understood. Now, Chaogu Zheng, Martin Chalfie and colleagues show that, rather than collaborate, Hsps and the UPS counter each other during neuronal development in Caenorhabditis elegans. Isolated from a genetic suppressor screen, the F-Box protein (and thus UPS component) MEC-15 stabilises microtubules and promotes neurite growth in touch receptor neurons (TRNs). Deletion of various Hsps and their regulators rescues mec-15(-) neurite growth defects, microtubule loss and sensory defects; strong rescue was seen in the case of the Hsp co-chaperone sti-1 and the Hsp90-binding phosphatase pph-5. Phosphorylation inhibits STI-1 activity in TRNs, and PPH-5 dephosphorylation may counter this. The MAP3 kinase DLK-1 acts downstream of (and is stabilised by) STI-1 and PPH-5, and MEC-15 in turn limits the abundance of DLK-1 (but not STI-1 or PPH-5) in TRNs. MEC-15 also ensures proper synaptic function in motor neurons by similar antagonism of Hsps. Thus, a balanced antagonism between protein degradation and molecular chaperoning underlies C. elegans neuronal development.
A (heat) shock to the system: balancing chaperoning and degradation in developing neurons
A (heat) shock to the system: balancing chaperoning and degradation in developing neurons. Development 15 June 2020; 147 (12): e1202. doi:
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