Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions

ELife
Achim WernerMichael Rape

Abstract

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.

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Citations

Sep 8, 2018·Science·Elijah L MenaMichael Rape
Feb 21, 2021·Developmental Cell·Fernando Rodríguez-PérezMichael Rape
Mar 2, 2021·Acta Pharmaceutica Sinica. B·Yifan ChenMeidan Ying
Apr 4, 2021·International Journal of Molecular Sciences·Małgorzata Grzanka, Agnieszka Piekiełko-Witkowska
Dec 27, 2018·Seminars in Cell & Developmental Biology·Katerina Jerabkova, Izabela Sumara
Apr 24, 2021·Cell Chemical Biology·Predrag JevtićMichael Rapé
Dec 6, 2021·Journal of Molecular Biology·Megan C CohanRohit V Pappu

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Methods Mentioned

BETA
affinity-purification
affinity-purifications
pulldowns
RNAseq
fluorescence microscopy
PCR
gel filtration
transfections
immunoprecipitations
immunoprecipitation

Software Mentioned

PyMOL Molecular Graphics System
Image J
GraphPad
ConSurf
ImageJ
CompPASS
RaptorX
PyMOL

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