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

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

Abstract

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.

Citation

Amezquita, J., Desbois, M., Opperman, K. J., Pak, J. S., Christensen, E. L., Nguyen, N. T., Diaz-Garcia, K., Borgen, M. A., & Grill, B. (2024). Integrin adhesome axis inhibits the RPM-1 ubiquitin ligase signaling hub to regulate growth cone and axon development. PLOS genetics, 20(12), Article e1011496. https://doi.org/10.1371/journal.pgen.1011496

• Journal Article Type: Article
• Acceptance Date: Nov 12, 2024
• Online Publication Date: Dec 13, 2024
• Publication Date: Dec 13, 2024
• Deposit Date: Jan 9, 2025
• Publicly Available Date: Jan 9, 2025
• Journal: PLOS Genetics
• Print ISSN: 1553-7404
• Publisher: Public Library of Science (PLoS)
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Issue: 12
• Article Number: e1011496
• DOI: https://doi.org/10.1371/journal.pgen.1011496
• Public URL: https://keele-repository.worktribe.com/output/1021082