Integrin adhesome axis inhibits the RPM-1 ubiquitin ligase signaling hub to regulate growth cone and axon development

by Jonathan Amezquita, Muriel Desbois, Karla J. Opperman, Joseph S. Pak, Elyse L. Christensen, Nikki T. Nguyen, Karen Diaz-Garcia, Melissa A. Borgen, Brock Grill

Integrin signaling plays important roles in development and disease. An adhesion signaling network called the integrin adhesome has been principally defined using bioinformatics and cell-based proteomics. To date, the adhesome has not been studied using integrated proteomic and genetic approaches. Here, proteomic studies in C. elegans identified physical associations between the RPM-1 ubiquitin ligase signaling hub and numerous adhesome components including Talin (TLN-1), Kindlin (UNC-112) and β-integrin (PAT-3). C. elegans RPM-1 is orthologous to human MYCBP2, a prominent player in nervous system development recently associated with a neurodevelopmental disorder. After curating and updating the conserved C. elegans adhesome, we identified an adhesome subnetwork physically associated with RPM-1 that has extensive links to human neurobehavioral abnormalities. Using neuron-specific, CRISPR loss-of-function strategies, we demonstrate that a PAT-3/UNC-112/TLN-1 adhesome axis regulates axon termination in mechanosensory neurons by inhibiting RPM-1. Developmental time-course studies and pharmacological results suggest TLN-1 inhibition of RPM-1 affects growth cone collapse and microtubule dynamics during axon outgrowth. These results indicate the PAT-3/UNC-112/TLN-1 adhesome axis restricts RPM-1 signaling to ensure axon outgrowth is terminated in a spatially and temporally accurate manner. Thus, our findings orthogonally validate the adhesome using an organismal setting, identify an adhesome axis that inhibits RPM-1 (MYCBP2), and highlight important new links between the adhesome and brain disorders.