DNA-damage inducible 1 homolog 2 (DDI2) is a protease that activates the transcription factor NRF1. Cellular models have shown that this pathway contributes to cell-stress adaptation, for example, on proteasome inhibition. However, DDI2 physiological function is unknown. Ddi2 Knock-out (KO) mice were embryonic lethal. Therefore, we generated liver-specific Ddi2-KO animals and used comprehensive genetic analysis to identify the molecular pathways regulated by DDI2. Here, we demonstrate that DDI2 contributes to metallothionein (MT) expression in mouse and human hepatocytes at basal and upon cadmium (Cd) exposure. This transcriptional program is dependent on DDI2-mediated NRF1 proteolytic maturation. In contrast, NRF1 homolog NRF2 does not contribute to MT production. Mechanistically, we observed that Cd exposure inhibits proteasome activity, resulting in DDI2-mediated NRF1 proteolytic maturation. In line with these findings, DDI2 deficiency sensitizes cells to Cd toxicity. This study identifies a function for DDI2 that links proteasome homeostasis to heavy metal mediated toxicity.
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| http://dx.doi.org/10.1016/j.isci.2022.105227 | DOI Listing |
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Article Synopsis
- Nuclear factor erythroid 2 like 1 (NFE2L1 or NRF1) is a transcription factor that controls the expression of proteasome components and their assembly helpers.
- The study reveals that the E3 ligase UBE4A is crucial for tagging NRF1 with ubiquitin, which is necessary for its activation by the protease DDI2 after NRF1 is retrotranslocated from the endoplasmic reticulum to the cytosol.
- A lack of UBE4A leads to reduced ubiquitination of NRF1, resulting in decreased NRF1 activation and lower transcription of proteasomal subunits, highlighting UBE4A's role in modulating NRF1 function.
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