A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development

Anthony J. Asmar, Shaun R. Abrams, Jenny Hsin, Jason C. Collins, Rita M. Yazejian, Youmei Wu, Jean Cho, Andrew D. Doyle, Samhitha Cinthala, Marleen Simon, Richard H. Jaarsveld, David B. Beck, Laura Kerosuo () and Achim Werner ()
Additional contact information
Anthony J. Asmar: National Institutes of Health
Shaun R. Abrams: National Institutes of Health
Jenny Hsin: National Institutes of Health
Jason C. Collins: National Institutes of Health
Rita M. Yazejian: National Institutes of Health
Youmei Wu: National Institutes of Health
Jean Cho: National Institutes of Health
Andrew D. Doyle: National Institutes of Health
Samhitha Cinthala: National Institutes of Health
Marleen Simon: University Medical Center Utrecht
Richard H. Jaarsveld: University Medical Center Utrecht
David B. Beck: New York University Grossman School of Medicine
Laura Kerosuo: National Institutes of Health
Achim Werner: National Institutes of Health

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The molecular mechanisms that coordinate patterning of the embryonic ectoderm into spatially distinct lineages to form the nervous system, epidermis, and neural crest-derived craniofacial structures are unclear. Here, biochemical disease-variant profiling reveals a posttranslational pathway that drives early ectodermal differentiation in the vertebrate head. The anteriorly expressed ubiquitin ligase CRL3-KLHL4 restricts signaling of the ubiquitous cytoskeletal regulator CDC42. This regulation relies on the CDC42-activating complex GIT1-βPIX, which CRL3-KLHL4 exploits as a substrate-specific co-adaptor to recognize and monoubiquitylate PAK1. Surprisingly, we find that ubiquitylation converts the canonical CDC42 effector PAK1 into a CDC42 inhibitor. Loss of CRL3-KLHL4 or a disease-associated KLHL4 variant reduce PAK1 ubiquitylation causing overactivation of CDC42 signaling and defective ectodermal patterning and neurulation. Thus, tissue-specific restriction of CDC42 signaling by a ubiquitin-based effector-to-inhibitor is essential for early face, brain, and skin formation, revealing how cell-fate and morphometric changes are coordinated to ensure faithful organ development.

Date: 2023
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DOI: 10.1038/s41467-023-40223-y

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