DDI2 protease controls embryonic development and inflammation via TCF11/NRF1
DDI2 is an aspartic protease that cleaves polyubiquitinated substrates. Upon proteotoxic stress, DDI2 activates the transcription factor TCF11/NRF1 (NFE2L1), crucial for maintaining proteostasis in mammalian cells, enabling the expression of rescue factors, including proteasome subunits. Here, we describe the consequences of DDI2 ablation <i>in vivo</i> and in cells. DDI2 knock-out (KO) in mice caused embryonic lethality at E12.5 with severe developmental failure. Molecular characterization of embryos showed insufficient proteasome expression with proteotoxic stress, accumulation of high molecular weight ubiquitin conjugates and induction of the unfolded protein response (UPR) and cell death pathways. In <i>DDI2</i> surrogate KO cells, proteotoxic stress activated the integrated stress response (ISR) and induced a type I interferon (IFN) signature and IFN-induced proliferative signaling, possibly ensuring survival. These results indicate an important role for DDI2 in the cell-tissue proteostasis network and in maintaining a balanced immune response.
Authors
- Jan Konvalinka (ORCID: https://orcid.org/0000-0003-0695-9266)
- Stefanie Haberecht-Müller
- Kallayanee Chawengsaksophak (ORCID: https://orcid.org/0000-0001-9401-2122)
- Simone Venz
- Klára Grantz Šašková (ORCID: https://orcid.org/0000-0003-2874-5699)
- Radislav Sedláček (ORCID: https://orcid.org/0000-0002-3352-392X)
- Michaela Procházková (ORCID: https://orcid.org/0000-0002-4229-9202)
- František Sedlák (ORCID: https://orcid.org/0000-0002-5565-8462)
- Elke Hammer (ORCID: https://orcid.org/0000-0002-1507-0402)
- Petr Kašpárek (ORCID: https://orcid.org/0000-0001-6047-7538)
- Monika Nedomova (ORCID: https://orcid.org/0000-0002-7327-9917)
- Michael Adamek
- Jan Procházka
- Sophie Möller (ORCID: https://orcid.org/0009-0004-0353-6457)
- Elke Krüger (ORCID: https://orcid.org/0000-0002-2551-242X)
Institutions
- Charles University (CZ)
- Universitätsmedizin Greifswald (DE)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
Publication Details
- Journal
- iScience
- Published
- 2024-09-06
- DOI
- https://doi.org/10.1016/j.isci.2024.110893
- Citations
- 5
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- Univerzita Karlova v Praze
- Deutsche Forschungsgemeinschaft
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Akademie Věd České Republiky