DDI2 protease controls embryonic development and inflammation via TCF11/NRF1.

Autor:	Nedomova M; Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague, Czech Republic.; First Faculty of Medicine, Charles University in Prague, Katerinska 32, 121 08 Prague, Czech Republic.; Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25242 Vestec, Czech Republic., Haberecht-Müller S; Institute of Medical Biochemistry and Molecular Biology, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, Klinikum DZ 7, 17475 Greifswald, Germany., Möller S; Institute of Medical Biochemistry and Molecular Biology, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, Klinikum DZ 7, 17475 Greifswald, Germany., Venz S; Institute of Medical Biochemistry and Molecular Biology, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, Klinikum DZ 7, 17475 Greifswald, Germany., Prochazkova M; Department of Functional Genomics, Universitätsmedizin Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany., Prochazka J; Department of Functional Genomics, Universitätsmedizin Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany., Sedlak F; Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague, Czech Republic.; First Faculty of Medicine, Charles University in Prague, Katerinska 32, 121 08 Prague, Czech Republic.; Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25242 Vestec, Czech Republic., Chawengsaksophak K; Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, BIOCEV, 25242 Vestec, Czech Republic., Hammer E; Department of Functional Genomics, Universitätsmedizin Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany., Kasparek P; Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, BIOCEV, 25242 Vestec, Czech Republic., Adamek M; Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague, Czech Republic.; Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25242 Vestec, Czech Republic., Sedlacek R; Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases, BIOCEV, 25242 Vestec, Czech Republic., Konvalinka J; Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague, Czech Republic., Krüger E; Institute of Medical Biochemistry and Molecular Biology, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, Klinikum DZ 7, 17475 Greifswald, Germany., Grantz Saskova K; Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague, Czech Republic.; Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25242 Vestec, Czech Republic.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 Sep 05; Vol. 27 (10), pp. 110893. Date of Electronic Publication: 2024 Sep 05 (Print Publication: 2024).
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. Competing Interests: The authors declare that they have no conflict of interest. (© 2024 The Author(s).)
Databáze:	MEDLINE
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