Immune cells avoid death from immunoproteasome inhibitors by switching to conventional proteasome

Abstract

Abstract The pan-proteasome inhibitor bortezomib has demonstrated sustained clinical efficacy in off label trials in SLE patients by depleting pathogenic immune cells including highly secretory plasmablasts and plasmacytoid dendritic cells. But bortezomib also effects non-immune cells including neurons which raises significant safety concerns thus limiting the feasibility of pan-proteasome inhibitors as a treatment for autoimmune disease. As an alternative, targeting the immune cell specific immunoproteasome has been proposed as a promising therapy to deplete pathogenic immune cells while avoiding toxicity issues. Using highly specific immunoproteasome inhibitors, we show that this strategy does not lead to immune cell death as anticipated. We generated a large panel of small molecule inhibitors with varying specificity to the β5 subunit of the conventional and immuno- proteasome, and found that effects on viability of plasmablasts and pDCs correlate with the inhibition of the conventional proteasome, not the immunoproteasome. Our data indicates that the immune cells upregulate the conventional proteasomal subunits and prevent the accumulation of ubiquitinated protein. Widely used immunoproteasome inhibitors also block the conventional proteasome which, our data would indicate, is key to their ability to deplete immune cells.