Timely elimination of misfolded and damaged proteins is essential to maintaining cellular protein homeostasis. A functional decline in the proteolytic capacity of a cell leads to the accumulation of highly toxic protein aggregates that underlies the development of protein misfolding diseases such as Alzheimer’s and Huntington’s disease. The ubiquitin proteasome system (UPS) is the main cellular pathway for protein degradation where proteins modified by specific ubiquitin (Ub) signals such as K48-linked polyUb are targeted for degradation by the proteasome. We recently discovered a new DUB family, named MINDY, in mammalian cells. Interestingly, two members of this family are conserved down to yeast, and all MINDY DUBs are highly selective at cleaving K48-linked polyUb. 

To understand the cellular role of this uncharacterized family of DUBs, we used S. cerevisiae, a powerful tool in the study of pathways regulating protein quality control and homeostasis. Being selective at cleaving K48-linked polyubiquitin, we hypothesized that MINDY DUBs are negative regulators of protein degradation. Indeed, yeast strains lacking MINDY (miy∆) exhibit increased proteolytic capacity as assessed by degradation of model substrates. Excitingly, our results reveal that miy∆ strains not only have an extended chronological LifeSpan (CLS) but also exhibit an improved replicative LifeSpan. A decline in the proteolytic capacity of a cell is known to result in the accumulation of toxic protein aggregates, one of the underlying causes of ageing and age-related proteinopathies. Indeed, while wild type yeast cells accumulate protein aggregates with age, aged miy∆ cells have hardly any detectable protein aggregates. 

In summary, our exciting results reveal that MINDY DUBs are hitherto unstudied important regulators of proteostasis. Further, by studying MINDY DUBs in human cells, my work reveals that the mechanism of action is evolutionarily conserved. Importantly, our results reveal that MINDY DUBs maybe an attractive therapeutic target in neurodegeneration.