Definition of a transcriptional signature of proteasome stress across cell types and its occurrence with aging [RNA-Seq human]

Proteasome inhibition triggers a compensatory increase in proteasome gene expression, but it is largely undetermined whether this is the primary response induced by proteasome inhibition. Here, we profiled the transcriptional changes induced by chemical and genetic proteasome inhibition.

By examining the time-dose response to proteasome inhibition in cells and organoids, we find that modulation of proteasome gene expression varies in a context-dependent manner, and that other categories are more prominently and consistently regulated by proteasome inhibition. These include upregulation of chaperones and secreted factors, and downregulation of cell cycle regulators. Moreover, we define a proteasome stress response signature based on genes that are significantly and consistently modulated by proteasome inhibition across different cell systems.