Spotlights

Schematic representation of NRF1-triggered activation of aggrephagy mediated by impaired proteasome activity
The ubiquitin‒proteasome system (UPS) and autophagy are protein degradation pathways essential for maintaining protein balance and regulation, or proteostasis (left panel). When proteasome activity decreases because of several reasons including chemical inhibitors and aging, the transcription factor NRF1 gets activated, leading to the upregulation of proteasome gene expression (“the proteasome bounce-back response;” middle panel). Furthermore, complete proteasome dysfunction activates NRF1-mediated aggrephagy, inducing the expression of the aggrephagy-related genes p62 and GABARAPL1 (right). These cellular responses help combat proteasome dysfunction by maintaining proteostasis.

Atsushi Hatanaka, a graduate student, and Akira Kobayashi, a professor, both from the Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, and their research team discovered the hidden mechanism of "aggrephagy," with major implications for degenerative protein diseases.
In cells, the ubiquitin‒proteasome system (UPS) plays a key role in the elimination of unwanted or misfolded proteins. When UPS fails, cells activate a backup process called "aggrephagy" for clearing ubiquitin-tagged proteins. However, the associated mechanism behind this process remains unknown. Recently, Hatanaka, Kobayashi, and their colleagues have demonstrated how another protein called NRF1 facilitates aggrephagy, thereby providing new therapeutic targets for diseases resulting from misfolded proteins.
These findings pave the way toward developing novel therapeutics for degenerative diseases such as Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies.