AI Insight
This study identifies two ER-resident selenoproteins, SELS and SELK, as cooperative regulators of NRF1, a transcription factor responsible for restoring proteasome levels when the cell's protein degradation system is impaired. SELS was found to stabilize NRF1 protein, while SELK promotes its insolubilization, with the loss of either protein leading to abnormal accumulation and increased nuclear activity of NRF1. Together, these selenoproteins appear to control NRF1's retrotranslocation from the ER membrane and its solubility, thereby gating how strongly cells can activate proteasome subunit gene expression.
Why it matters
Understanding how selenoproteins regulate proteasome recovery pathways may have implications for diseases linked to proteostasis failure, including neurodegeneration and cancer, and could inform strategies targeting ER-associated degradation mechanisms therapeutically.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
NRF1 is a key mediator of the proteasome recovery pathway, yet its regulation by ER-resident factors is not fully elucidated. Here, we demonstrate that selenoproteins SELS and SELK are critical regulators for NRF1 protein dynamics. SELS stabilizes NRF1, while SELK induces its insolubilization. Their deficiency leads to a hyper-accumulation and increased nuclear localization of NRF1 under proteasome inhibition condition. This results in an augmented transcriptional response of proteasome subunits. These results indicate that SELS and SELK cooperatively gate NRF1 activity by controlling its retrotranslocation and solubility, highlighting a novel layer of selenoprotein-mediated quality control in the proteostasis network.