Design and Evaluation of Highly Selective Human Immunoproteasome Inhibitors Reveal a Compensatory Process That Preserves Immune Cell Viability

The pan-proteasome
inhibitor bortezomib demonstrated clinical efficacy
in off-label trials of Systemic Lupus Erythematosus. One potential
mechanism of this clinical benefit is from the depletion of pathogenic
immune cells (plasmablasts and plasmacytoid dendritic cells). However,
bortezomib is cytotoxic against nonimmune cells, which limits its
use for autoimmune diseases. An attractive alternative is to selectively
inhibit the immune cell-specific immunoproteasome to deplete pathogenic
immune cells and spare nonhematopoietic cells. Here, we disclose the
development of highly subunit-selective immunoproteasome inhibitors
using insights obtained from the first bona fide human immunoproteasome
cocrystal structures. Evaluation of these inhibitors revealed that
immunoproteasome-specific inhibition does not lead to immune cell
death as anticipated and that targeting viability requires inhibition
of both immuno- and constitutive proteasomes. CRISPR/Cas9-mediated
knockout experiments confirmed upregulation of the constitutive proteasome
upon disruption of the immunoproteasome, protecting cells from death.
Thus, immunoproteasome inhibition alone is not a suitable approach
to deplete immune cells.