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

Autor: Amezquita J; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, United States of America., Desbois M; School of Life Sciences, Keele University, Keele, Staffordshire, United Kingdom., Opperman KJ; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America., Pak JS; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America., Christensen EL; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, United States of America., Nguyen NT; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America., Diaz-Garcia K; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America., Borgen MA; Florida Institute of Technology, Department of Biomedical Engineering and Sciences, Melbourne, United States of America., Grill B; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, United States of America.; Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2024 Dec 13; Vol. 20 (12), pp. e1011496. Date of Electronic Publication: 2024 Dec 13 (Print Publication: 2024).
DOI: 10.1371/journal.pgen.1011496
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Amezquita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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