Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions
Achim Werner,
Regina Baur,
Nia Teerikorpi,
Deniz U Kaya,
Michael Rape
Affiliations
Achim Werner
Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Nia Teerikorpi
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8. We found that CUL3KBTBD8 monoubiquitylates its essential targets only after these have been phosphorylated in multiple motifs by CK2, a kinase whose levels gradually increase during embryogenesis. Its dependency on multisite phosphorylation allows CUL3KBTBD8 to convert the slow rise in embryonic CK2 into decisive recognition of ubiquitylation substrates, which in turn is essential for neural crest specification. We conclude that multisite dependency of an E3 ligase provides a powerful mechanism for switch-like cell fate transitions controlled by monoubiquitylation.
