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.

1st Faculty of Medicine Charles University Prague Katerinska 32 121 08 Prague Czech Republic

Department of Functional Genomics Universitätsmedizin Greifswald Felix Hausdorff Str 8 17475 Greifswald Germany

Department of Genetics and Microbiology Faculty of Science Charles University BIOCEV 25242 Vestec Czech Republic

Institute of Medical Biochemistry and Molecular Biology Universitätsmedizin Greifswald Ferdinand Sauerbruch Straße Klinikum DZ 7 17475 Greifswald Germany

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

Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic Flemingovo n 2 166 10 Prague Czech Republic

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