Osa DDI2-NRF1 v regulaci proteotoxického stresu

Sedláček, Jindřich

Nuclear factor-erythroid 2-like bZIP factor 1 (NFE2L1, also known as NRF1), a member of the cap'n'collar family of transcription factors, is a crucial regulator that mediates adaptive responses to various cellular stresses and helps maintain homeostasis and organ integrity during development. Under proteasome inhibitor treatment, NRF1 switches on the coordinated expression of 26S proteasome subunit genes in a concerted manner, a phenomenon also known as the "proteasome bounce-back" response, which is especially significant in multiple myeloma. This adaptive response often leads to resistance against proteasome inhibitors. NRF1 also supports cell proliferation, metabolic reprogramming, and buffering of high proteotoxic stress, which is typical for various malignancies. Conversely, impaired protein degradation in neural tissues is associated with numerous neurodegenerative diseases. Therefore, better understanding the functional mechanisms of NRF1-mediated signalling and its proteolytic activator DDI2, collectively referred to as the DDI2-NRF1 axis, in regulating protein degradation through the ubiquitin-proteasome system and autophagy is essential for the development of novel strategies to prevent and treat these disorders. Therefore, potential regulators of NRF1 may hold unique potential for...

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