Ddi2, an aspartic protease, is crucial in multiple biological processes. It cleaves polyubiquitinated substrates, and is involved in pathways such as proteostasis regulation via activating transcription factor TCF11/NRF1 [2,4,5,6,7]. It also plays a role in angiogenesis by proteolytically activating angiomotin (AMOT) [1]. Ddi2 is associated with important biological functions like embryonic development and is linked to diseases such as colorectal cancer [1,2,3].

Ddi2 knockout (KO) in mice led to embryonic lethality at E12.5 due to severe developmental failure, with insufficient proteasome expression, proteotoxic stress, and induction of cell death pathways [2]. Liver-specific Ddi2-KO mice showed that DDI2 contributes to metallothionein expression upon cadmium exposure, and its deficiency sensitizes cells to cadmium toxicity [4]. In colorectal cancer, depression of DDI2 inhibited cell proliferation, migration, and invasion both in vitro and in vivo, suggesting its role in carcinogenesis [3].

In conclusion, Ddi2 is essential for maintaining proteostasis, embryonic development, and is involved in angiogenesis and carcinogenesis. Studies using Ddi2 KO mouse models have revealed its role in these biological processes and disease conditions, providing valuable insights into potential therapeutic targets for diseases like colorectal cancer [2,3,4].

References:

1. Wang, Yu, Zhu, Yuwen, Wang, Yebin, Zhang, Ruilin, Yu, Fa-Xing. 2023. Proteolytic activation of angiomotin by DDI2 promotes angiogenesis. In The EMBO journal, 42, e112900. doi:10.15252/embj.2022112900. https://pubmed.ncbi.nlm.nih.gov/37350545/

2. Nedomova, Monika, Haberecht-Müller, Stefanie, Möller, Sophie, Krüger, Elke, Grantz Saskova, Klara. 2024. DDI2 protease controls embryonic development and inflammation via TCF11/NRF1. In iScience, 27, 110893. doi:10.1016/j.isci.2024.110893. https://pubmed.ncbi.nlm.nih.gov/39328932/

3. Lei, Lei, Cao, Qing, An, Guoyan, Tang, Juan, Yang, Jin. 2022. DDI2 promotes tumor metastasis and resists antineoplastic drugs-induced apoptosis in colorectal cancer. In Apoptosis : an international journal on programmed cell death, 28, 458-470. doi:10.1007/s10495-022-01796-z. https://pubmed.ncbi.nlm.nih.gov/36520320/

4. Ribeiro, Sérgio T, de Gassart, Aude, Bettigole, Sarah, Nugraha, Kalvin, Martinon, Fabio. 2022. The protease DDI2 regulates NRF1 activation in response to cadmium toxicity. In iScience, 25, 105227. doi:10.1016/j.isci.2022.105227. https://pubmed.ncbi.nlm.nih.gov/36248746/

5. Dirac-Svejstrup, A Barbara, Walker, Jane, Faull, Peter, Powell, David J, Svejstrup, Jesper Q. 2020. DDI2 Is a Ubiquitin-Directed Endoprotease Responsible for Cleavage of Transcription Factor NRF1. In Molecular cell, 79, 332-341.e7. doi:10.1016/j.molcel.2020.05.035. https://pubmed.ncbi.nlm.nih.gov/32521225/

6. Yoshida, Yukiko, Takahashi, Tsuyoshi, Ishii, Nozomi, Tanaka, Keiji, Suzuki, Tadashi. 2024. Sugar-mediated non-canonical ubiquitination impairs Nrf1/NFE2L1 activation. In Molecular cell, 84, 3115-3127.e11. doi:10.1016/j.molcel.2024.07.013. https://pubmed.ncbi.nlm.nih.gov/39116872/

7. Op, Mélanie, Ribeiro, Sérgio T, Chavarria, Claire, Zaffalon, Léa, Martinon, Fabio. 2022. The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma. In Cell death & disease, 13, 475. doi:10.1038/s41419-022-04925-3. https://pubmed.ncbi.nlm.nih.gov/35589686/