Unfolding or aggregation, that is the question

Abstract

Cellular processes accompanying protein aggregation are diverse and entangled, making it difficult to investigate the underlying molecular processes in a time-resolved way. Gottlieb, Thompson, and colleagues address this shortcoming using a chemical biology approach to monitor ubiquitination within the first 10 min after the initiation of protein aggregation. Intriguingly, unfolding rather than aggregation seems to trigger the observed events. This work might provide a method to answer open questions regarding the regulation of the proteostasis network upon protein misfolding.

Figure 1.

A, AgDD remains soluble in the presence of S1 but readily aggregates upon S1 washout. B, AgDD unfolding stimulates UBE3C recruitment to the 26S proteasome, leading to increased ubiquitination of AgDD, perhaps to increase substrate processivity, and increased RPN13 ubiquitination, to potentially prevent the recruitment of other proteasome substrates to the engaged particle. When the cell is not overloaded with misfolded proteins, these other substrates would then be degraded by other—nonengaged—proteasome particles. NES, nuclear export signal; sfGFP, superfolder GFP.