0598945 - ÚOCHB 2025 RIV US eng J - Journal Article
Nedomová, Monika - Haberecht-Müller, S. - Möller, S. - Venz, S. - Procházková, M. - Procházka, J. - Sedlák, František - Chawengsaksophak, Kallayanee - Hammer, E. - Kašpárek, Petr - Adámek, Michael - Sedláček, Radislav - Konvalinka, Jan - Krüger, E. - Grantz Šašková, Klára
DDI2 protease controls embryonic development and inflammation via TCF11/NRF1.
iScience. Roč. 27, č. 10 (2024), č. článku 110893. E-ISSN 2589-0042
R&D Projects: GA ČR(CZ) GA22-16389S; GA MŠMT LM2023036; GA MŠMT EF18_046/0015861
Institutional support: RVO:61388963 ; RVO:68378050
Keywords : bZIP transcription factor * TANK-binding kinase-1 * interferon
OECD category: Biochemistry and molecular biology
Impact factor: 4.6, year: 2023 ; AIS: 1.5, rok: 2023
Method of publishing: Open access
Result website:
https://doi.org/10.1016/j.isci.2024.110893DOI: https://doi.org/10.1016/j.isci.2024.110893

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 in vivo 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 DDI2 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.
Permanent Link: https://hdl.handle.net/11104/0356512


Research data: IMPC