DDI2 protease controls embryonic development and inflammation via TCF11/NRF1

Autor
Haberecht-Müller, Stefanie
Möller, Sophie
Venz, Simone
Procházková, Michaela
Procházka, Jan
Chawengsaksophak, Kallayanee
Hammer, Elke
Elke, Kruger
Datum vydání
2024Publikováno v
iScienceRočník / Číslo vydání
27 (10)ISBN / ISSN
ISSN: 2589-0042ISBN / ISSN
eISSN: 2589-0042Metadata
Zobrazit celý záznamKolekce
Tato publikace má vydavatelskou verzi s DOI 10.1016/j.isci.2024.110893
Abstrakt
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.
Klíčová slova
DDI2 protease, proteasome, ubiquitin, ubiquitin protease, TCF11/NRF1, NFE2L1, knock-out, interferon, bZIP transcription factor, tank-binding kinase-1
Trvalý odkaz
https://hdl.handle.net/20.500.14178/2650Licence
Licence pro užití plného textu výsledku: Creative Commons Uveďte původ-Neužívejte dílo komerčně 4.0 International