Carboxy-terminal polyglutamylation regulates signaling and phase separation of the Dishevelled protein
Polyglutamylation is a reversible posttranslational modification that is catalyzed by enzymes of the tubulin tyrosine ligase-like (TTLL) family. Here, we found that TTLL11 generates a previously unknown type of polyglutamylation that is initiated by the addition of a glutamate residue to the free C-terminal carboxyl group of a substrate protein. TTLL11 efficiently polyglutamylates the Wnt signaling protein Dishevelled 3 (DVL3), thereby changing the interactome of DVL3. Polyglutamylation increases the capacity of DVL3 to get phosphorylated, to undergo phase separation, and to act in the noncanonical Wnt pathway. Both carboxy-terminal polyglutamylation and the resulting reduction in phase separation capacity of DVL3 can be reverted by the deglutamylating enzyme CCP6, demonstrating a causal relationship between TTLL11-mediated polyglutamylation and phase separation. Thus, C-terminal polyglutamylation represents a new type of posttranslational modification, broadening the range of proteins that can be modified by polyglutamylation and providing the first evidence that polyglutamylation can modulate protein phase separation.
Authors
- Miroslav Micka (ORCID: https://orcid.org/0000-0003-3343-8060)
- Zbyněk Zdráhal (ORCID: https://orcid.org/0000-0003-3044-5548)
- Nikodém Zezula (ORCID: https://orcid.org/0009-0006-0539-8937)
- Kristína Gömöryová (ORCID: https://orcid.org/0000-0003-4407-3917)
- Sara Bologna (ORCID: https://orcid.org/0000-0002-2709-8322)
- Igor Červenka (ORCID: https://orcid.org/0000-0002-9438-5161)
- Sri Ranjani Ganji (ORCID: https://orcid.org/0000-0002-9655-3069)
- Jana Nedvědová (ORCID: https://orcid.org/0000-0001-5761-0764)
- Marek Kravec (ORCID: https://orcid.org/0000-0002-5757-2291)
- Vı́tězslav Bryja (ORCID: https://orcid.org/0000-0002-9136-5085)
- Marie Šulcová (ORCID: https://orcid.org/0000-0002-9642-8129)
- Jakub Harnoš (ORCID: https://orcid.org/0000-0002-0752-9260)
- Cyril Bařinka (ORCID: https://orcid.org/0000-0003-2751-3060)
- Konstantinos Tripsianes (ORCID: https://orcid.org/0000-0003-0948-813X)
- Ondřej Šedo (ORCID: https://orcid.org/0000-0002-5091-2978)
- David Potěšil (ORCID: https://orcid.org/0000-0003-0390-0904)
- Carsten Janke (ORCID: https://orcid.org/0000-0001-7053-2000)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Central European Institute of Technology (CZ)
- Charles University (CZ)
- Masaryk University (CZ)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Institut Curie (FR)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1038/s44318-024-00254-7
- Citations
- 12
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- Univerzita Karlova v Praze
- Grantová Agentura, Univerzita Karlova
- European Commission
- Agence Nationale de la Recherche
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Akademie Věd České Republiky
- Central European Institute of Technology
- European Regional Development Fund