Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.

Cells must constantly destroy proteins that are damaged, abnormal, or no longer needed. This process is essential for human health; failure to remove damaged or abnormal proteins contributes to many diseases including age-dependent neurodegenerative disorders. We aimed to understand how cells ensure this system works efficiently, even when it is placed under stress. Using a genetic strategy in the microscopic nematode worm C. elegans, we found that a highly conserved protein called EEL-1 (which is equivalent to a protein called HUWE1 in humans) plays a role to help ensure efficient protein destruction when the system is challenged. Large parts of the EEL-1 protein - in regions called lysine deserts - lack the amino acid lysine. We found that, like other proteins involved in protein removal, lysine deserts are important for EEL-1 function. In fact, introducing lysine into its lysine desert causes self-destruction of EEL-1 through the very protein destruction system that it helps operate. Our results shed new light on how EEL-1 helps cells maintain efficient protein destruction, which may be useful for future efforts to develop treatments for diseases in which this process fails.