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Updated: Jun 12, 2025
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Study of Dendritic Cell Development by Short Hairpin RNA-Mediated Gene Knockdown in a Hematopoietic Stem and Progenitor Cell Line In vitro
Published on: March 7, 2022
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DDI2 protease controls embryonic development and inflammation via TCF11/NRF1
Monika Nedomova1,2,3, Stefanie Haberecht-Müller4, Sophie Möller4
1Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague, Czech Republic.
Iscience
|September 27, 2024
Summary
The aspartic protease DDI2 is essential for cellular proteostasis and embryonic development. Its absence causes developmental failure and triggers stress responses, highlighting DDI2
Area of Science:
- Molecular Biology
- Cell Biology
- Developmental Biology
Background:
- DDI2 is an aspartic protease that cleaves polyubiquitinated substrates.
- DDI2 activates transcription factor TCF11/NRF1 (NFE2L1) upon proteotoxic stress.
- This activation is crucial for maintaining proteostasis and expressing rescue factors like proteasome subunits.
Purpose of the Study:
- To investigate the in vivo and cellular consequences of DDI2 ablation.
- To understand DDI2's role in the proteostasis network and immune response.
Main Methods:
- DDI2 knock-out (KO) mouse model.
- Cellular studies using DDI2 surrogate KO cells.
- Molecular characterization of embryonic tissues and cells under proteotoxic stress.
Main Results:
- DDI2 KO mice exhibited embryonic lethality at E12.5 with severe developmental failure.
- Embryos showed insufficient proteasome expression, ubiquitin conjugate accumulation, and UPR induction.
- DDI2-deficient cells displayed ISR activation, a type I interferon signature, and IFN-induced proliferative signaling.
Conclusions:
- DDI2 plays a critical role in embryonic development and cellular proteostasis.
- DDI2 is important for maintaining a balanced immune response.
- Ablation of DDI2 leads to proteotoxic stress, developmental failure, and altered immune signaling.
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