PDZ-RhoGEF ubiquitination by Cullin3–KLHL20 controls neurotrophin-induced neurite outgrowth

Abstract

Ubiquitin-dependent degradation of PDZ-RhoGEF restricts RhoA activity to facilitate neurite outgrowth.

Abstract

The induction of neurite outgrowth and arborization is critical for developmental and regenerative processes. In this paper, we report that the BTB-kelch protein KLHL20 promoted neurite outgrowth and arborization in hippocampal and cortical neurons through its interaction with Cullin3 to form a ubiquitin ligase complex. This complex targeted PDZ–Rho guanine nucleotide exchange factor (RhoGEF), a protein abundantly expressed in the brain, for ubiquitin-dependent proteolysis, thereby restricting RhoA activity and facilitating growth cone spreading and neurite outgrowth. Importantly, targeting PDZ-RhoGEF to KLHL20 required PDZ-RhoGEF phosphorylation by p38 mitogen-activated protein kinase. In response to p38-activating neurotrophins, such as brain-derived neurotrophic factor and neurotrophin-3, KLHL20-mediated PDZ-RhoGEF destruction was potentiated, leading to neurotrophin-induced neurite outgrowth. Our study identified a ubiquitin-dependent pathway that targets PDZ-RhoGEF destruction to facilitate neurite outgrowth and indicates a key role of this pathway in neurotrophin-induced neuronal morphogenesis.