Global ubiquitinome profiling identifies NEDD4 as a regulator of Profilin 1 and actin remodelling in neural crest cells

• Published in: Nature communications Vol. 13; no. 1; p. 2018
• Main Authors: Lohraseb, Iman, McCarthy, Peter, Secker, Genevieve, Marchant, Ceilidh, Wu, Jianmin, Ali, Naveid, Kumar, Sharad, Daly, Roger J, Harvey, Natasha L, Kawabe, Hiroshi, Kleifeld, Oded, Wiszniak, Sophie, Schwarz, Quenten
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 19.04.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Actin; Actins - metabolism; Biology; Cancer; Cell survival; Cytoskeleton; Endosomal Sorting Complexes Required for Transport - metabolism; Gene expression; Lysine; Medical research; Morphology; Nedd4 Ubiquitin Protein Ligases - genetics; Nedd4 Ubiquitin Protein Ligases - metabolism; Nervous system; Neural crest; Neural Crest - metabolism; Neurosciences; Peptides; Peripheral nervous system; Polymerization; Profilin; Profilins - genetics; Profilins - metabolism; Proteins; Proteomes; Proteomics; Roles; Signal transduction; Stem cells; Systems development; Transcription factors; Transcriptomes; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29660-3

The ubiquitin ligase NEDD4 promotes neural crest cell (NCC) survival and stem-cell like properties to regulate craniofacial and peripheral nervous system development. However, how ubiquitination and NEDD4 control NCC development remains unknown. Here we combine quantitative analysis of the proteome, transcriptome and ubiquitinome to identify key developmental signalling pathways that are regulated by NEDD4. We report 276 NEDD4 targets in NCCs and show that loss of NEDD4 leads to a pronounced global reduction in specific ubiquitin lysine linkages. We further show that NEDD4 contributes to the regulation of the NCC actin cytoskeleton by controlling ubiquitination and turnover of Profilin 1 to modulate filamentous actin polymerization. Taken together, our data provide insights into how NEDD4-mediated ubiquitination coordinates key regulatory processes during NCC development.