Abstract
Platelets are megakaryocyte-derived acellular fragments prepped to maintain primary hemostasis and thrombosis by preserving vascular integrity. Although they lack nuclei, platelets harbor functional genomic mediators that bolster platelet activity in a signal-specific manner by performing limited de novo protein synthesis. Furthermore, despite their limited protein synthesis, platelets are equipped with multiple protein degradation mechanisms, such as the proteasome. In nucleated cells, the functions of the proteasome are well established and primarily include proteostasis among a myriad of other signaling processes. However, the role of proteasome-mediated protein degradation in platelets remains elusive. In this review article, we recapitulate the developing literature on the functions of the proteasome in platelets, discussing its emerging regulatory role in platelet viability and function and highlighting how its functional coupling with the transcription factor NF-κB constitutes a novel potential therapeutic target in atherothrombotic diseases.
Highlights
Platelets are anucleate blood fragments originating from maturing megakaryocytes— precursor cells derived from pluripotent hematopoietic stem cells [1,2]
Dupré et al [64] showed using PSI that the proteasome desensitizes platelets to the platelet-activating factor (PAF), a potent phospholipid mediator associated with multiple inflammatory diseases, via downregulating the ubiquitin-coupled PAF receptor upon ligand stimulation
Contravened by Koessler et al [108,126] who used different platelet agonist doses, bortezomib use conferred upon the proteolytic complex a role in collagen-mediated ATP release and ADP-induced platelet aggregation—the latter function being established by degrading eNOS regulators and preventing the production of NO, an ADP receptor antagonist [129]
Summary
Platelets are anucleate blood fragments originating from maturing megakaryocytes— precursor cells derived from pluripotent hematopoietic stem cells [1,2]. The execution of platelet function is met with a plethora of adhesive receptors (GPIb/IX/V complex, PSGL-1, GPVI immunoglobulin, α5β1/α2β1 integrins), activation receptors (protein tyrosine kinases, G-protein coupled receptors, αIIbβ integrin), secreted granule reservoirs (adhesion molecules, immunologic molecules, coagulation factors, chemokines, regulators of growth and angiogenesis, protease inhibitors, digestive enzymes, platelet agonists including ADP and Thromboxane A2, and platelet primers including epinephrine and soluble CD40L (sCD40L)), and dynamic cytoskeletal proteins (actin, myosin, spectrin) [26,27,28,29,30,31,32,33,34,35,36,37] Platelets inherit their cytoplasmic and membranous molecules from megakaryocytes early during platelet formation. The base comprises 2 nonATPase subunits and 6 homologous hexamer ring-forming ATPases (PSMC2/1/4/6/3/5) and is responsible for the assembly of the 19S regulatory particles with the 20S core particle, allowing the formation and activation of the ATP-dependent 26S proteasome. Assembled with the 19S regulatory particles to form the 26S proteasome, it degrades ubiquitin-conjugated proteins in an ATP-dependent manner (Figure 1). In contrast to the 26S proteasome, which harbors 19S regulatory subunits, the immunoproteasome is regulated by two heptameric 11S subunits, which consist of PA28 α/PSME1 and β/PSME2 subunits and are induced by interferon-γ [82,83] to facilitate substrate access into the proteasomal core [84,85]
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