Abstract
The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.
Highlights
The ubiquitin–proteasome system (UPS) is the main non-lysosomal pathway for the degradation of intracellular proteins. It consists of a sequence of enzymatic processes that tag a protein substrate with multiple ubiquitin molecules for subsequent degradation by the 26S proteasome, with the release of reusable ubiquitin performed by deubiquitinating enzymes (DUBs) (Figure 1) [1]
While constitutive proteasome (cP) is highly expressed in various tissues and its constitutive expression and formation is controlled on the transcriptional level through Nrf1/Tcf11 or inducible mainly upon proteotoxic stress, iP subunits are downregulated under these conditions [89,90,91]
The β5i/LMP7 subunit is known to be incorporated into 20S proteasome assembly intermediates, preferentially by higher affinity to the assembly factor proteasome maturation protein (POMP) [52]
Summary
The ubiquitin–proteasome system (UPS) is the main non-lysosomal pathway for the degradation of intracellular proteins. HSCs showself-renewal, low protein and synthesis poiesis [26] This requires tight regulation of quiescence, differ-[29], which increases underHSCs stressshow conditions and may lead to[29], the production of misfolded entiation [27,28]. Proteasome inhibition can target any of the three proteasome proteolytic sites—the caspase-like (β1), trypsin-like (β2), and chymotrypsin-like (β5) sites—whereby most of the PIs developed so far inhibit the β5/β5i subunits of the constitutive proteasome (cP) and the iP It remains unclear whether the specific thymoproteasome subunit β5t is affected by established PIs; its sensitivity to standard PIs has been shown to substantially differ from those of β5/β5i [43]. The Immunoproteasome: A Proteasomal Variant Linked to the Hematopoietic System
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