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Over the years, the proteasome has been extensively investigated due to its crucial roles in many important signaling pathways and its implications in diseases. Two proteasome inhibitors—bortezomib and carfilzomib—have received FDA approval for the treatment of multiple myeloma, thereby validating the proteasome as a chemotherapeutic target. As a result, further research efforts have been focused on dissecting the complex biology of the proteasome to gain the insight required for developing next-generation proteasome inhibitors.

It is clear that chemical probes have made significant contributions to these efforts, mostly by functioning as inhibitors that selectively block the catalytic activity of proteasomes. Analogues of these inhibitors are now providing additional tools for visualization of catalytically active proteasome subunits, several of which allow real-time monitoring of proteasome activity in living cells as well as in in vivo settings. These imaging probes will provide powerful tools for assessing the efficacy of proteasome inhibitors in clinical settings.

In this review, we will focus on the recent efforts towards developing imaging probes of proteasomes, including the latest developments in immunoproteasome-selective imaging probes. The proteasome is a key component of the ubiquitin proteasome pathway, which mediates the tightly controlled degradation of proteins involved in a myriad of cellular processes, including cell cycle regulation, apoptosis, immune responses, and malignant transformation [, ]. This multiprotease complex was validated as a chemotherapeutic target by the FDA approval of the first-generation proteasome inhibitor bortezomib (Velcade®). Since bortezomib’s approval in 2003, the second-generation proteasome inhibitor carfilzomib (Kyprolis®) has also been approved, and several others are in various stages of preclinical and clinical development. Each eukaryotic proteasome contains three distinct types of catalytically active subunits. The constitutive proteasome, containing catalytic subunits β1, β2, and β5, is expressed in all eukaryotic cells.

Based on their ability to hydrolyze fluorogenic peptide substrates, these subunits have been assigned caspase-like activity, trypsin-like activity, and chymotrypsin-like activity, respectively []. The immunoproteasome, an alternate form of the proteasome, is also expressed in hematopoietic cells and can be induced in other cell types by cytokines such as interferon-γ and tumor necrosis factor-α. During immunoproteasome assembly, β1i, β2i, and β5i are incorporated in place of their constitutive proteasome counterparts, thereby altering the catalytic activity of the resulting proteasome complex [, ] ().

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A third proteasome subtype, known as the thymoproteasome, has also been discovered in cortical thymic epithelial cells. Thymoproteasomes contain the immunoproteasome catalytic subunits β1i and β2i along with the thymoproteasome-specific catalytic subunit subunit β5t, and are suggested to function in the positive selection of T cells [].

Proteasome catalytic subunits are synthesized as inactive zymogens containing N-terminal propeptides. Removal of these propeptides upon completion of proteasome assembly is required to expose their catalytic residues [, ]. Since the discovery of proteasomes decades ago, our knowledge about the constitutive proteasome has been remarkably increased by extensive studies, which have revealed its crucial roles in many important cellular processes. More recently, the importance of the immunoproteasome in cells has gained recognition [].

Representation of the 20S proteasome complex, which is comprised of two outer α-rings and two inner β-rings, and an aerial view of β-rings containing either constitutive proteasome or immunoproteasome catalytic subunits. Aberrant regulation of the immunoproteasome is implicated in neurodegenerative diseases, autoimmune diseases, and cancers. While the immunoproteasome is suggested to primarily function in generating optimal peptides for MHC class I antigen presentation, other studies have suggested its involvement in additional processes as well [–]. Additionally, expression levels of immunoproteasome catalytic subunits are aberrantly regulated in a variety of diseases, including neurodegenerative and autoimmune diseases as well as cancers [–] [].

These findings have prompted the development of immunoproteasome-targeting inhibitors for treating these diseases, as well as for use as molecular probes to investigate immunoproteasome functions [, –]. However, much about the detailed cellular roles of immunoproteasomes remains to be understood.