B-cell malignancies express both the constitutive proteasome (c20s) and immunoproteasome (i20s) that differ by the catalytic subunits found in the β rings of the barrel (red for c20s, blue for i20s). As described in the text, these proteasomes regulate several functions in the cell, some that are specific to the immunoproteasome (found in the blue region) including Ag processing and cytokine production. Other functions of the proteasome may be specific to the c20s (red area) or are regulated by both (overlapping purple area). It remains to be determined whether functions of the proteasome such as NF-κB activation are regulated by one or both proteasomes. Having essential functions regulated by 2 proteasomes may explain why B-cell malignancies are so sensitive to this class of therapeutic agents. Professional illustration by A. Y. Chen.