Uncovering the Unexpected Role of Proteasome Activator PA200 in Regulating Immunoproteasome Expression and Activity

The proteasome activator PA200 binds to the catalytic core of both standard proteasome (s20S) and the immunoproteasome (i20S); however, whether PA200 uses the same mechanisms to activate i20S remains unknown. Our cryo-EM structures of the singly- and doubly-capped i20S-PA200 complexes and in vitro assays revealed that binding of the first PA200 induces an allosteric widening of the opposite unbound α-ring, resulting in a higher binding occupancy of the i20S and its stronger activation compared to the s20S. We also showed that in cells and tissues that express PA200, s20S and i20S, PA200 interacts preferably with i20S. Intriguingly, the expression of PA200 and the catalytic subunits of the i20S are differentially regulated, with PA200 playing a potential role in controlling the i20S subunits’ expression. This suggests that i20S function is fine-tuned by differential expression of PA200, and reveals an additional layer of i20S regulation.