COP9 Limits Dendritic Branching via Cullin3-Dependent Degradation of the Actin-Crosslinking BTB-Domain Protein Kelch

Abstract

Components of the COP9 signalosome (CSN), a key member of the conserved 26S proteasome degradation pathway, have been detected to be altered in patients of several debilitating syndromes. These findings suggest that CSN acts in neural circuits, but the exact function of CSN in brain remains unidentified. Previously, using Drosophila peripheral nervous system (PNS) as a model system, we determined that CSN is a critical regulator of dendritic morphogenesis. We found that defects in CSN led to the strikingly contrast phenotype of either reducing or stimulating dendritic branching. In particular, we have reported that CSN stimulates dendritic branching via Cullin1-mediated proteolysis. Here we describe that CSN inhibits dendritic arborization in PNS neurons acting via control of Cullin3 function: loss of Cullin3 causes excessive dendritic branching. We also identified a downstream target for Cullin3-dependent degradation in neurons – the actin-crosslinking BTB-domain protein Kelch. Inappropriate accumulation of Kelch, either due to the impaired Cullin3-dependent turnover, or ectopic expression of Kelch, leads to uncontrolled dendritic branching. These findings indicate that the CSN pathway modulates neuronal network in a multilayer manner, providing the foundation for new insight into the CSN role in human mental retardation disorders and neurodegenerative disease.

Cul3 and the BTB Adaptor Insomniac Are Key Regulators of Sleep Homeostasis and a Dopamine Arousal Pathway in Drosophila

“…Here we provided evidence that inc induction or Cul3-RNAi knockdown during development, but not exclusively during adulthood, could rescue (in the case of induction) or phenocopy (in the case of knockdown) their respective mutant/RNAi phenotypes. The Cul3 results are consistent with an established role for Cul3 in dendritic and axonal arborization, in which dendritic and axonal arborization are reduced in Cul3 mutants [29], [40]. Our data also revealed a stochastic branching defect in MB neurons in 26% of inc mutants, in which they lack a single α- or β-lobe.…”

Proteomic analysis of secreted saliva from Russian Wheat Aphid (Diuraphis noxia Kurd.) biotypes that differ in virulence to wheat

“…Three putative actinbinding and depolymerizing enzymes were found that are unique to D. noxia saliva and may play a role in preventing or resolving phloem obstructions. Kelch-like protein, most abundant in RWA5, was found to promote actin disassembly and rearrangement in Drosophila melanogaster [82,83]. Cofilin/ actin depolymerizing factor, observed only in RWA5, is an actin depolymerizing factor found in both plants and insects and is involved in actin depolymerization, signaling, and Golgi-mediated secretion [84,85].…”

Breaking It Down: The Ubiquitin Proteasome System in Neuronal Morphogenesis

“…Loss of Cul1 or of the F-box protein Slimb represses arborization, while loss of Cul3 enhances it, suggesting that the Cul1 and Cul3 E3 complexes target proteins with markedly different roles in dendritogenesis. One of the proposed targets for the Cul3 complex is Kelch, an actin cross-linking protein [76]. Mutation of Cul3 increases levels of Kelch protein, while mutation of Kelch reduces dendritic arborization and represses the Cul3 increased arborization phenotype [76], further establishing the complex link between the proteasome and the cytoskeleton.…”