Platelets, traditionally recognized for their role in haemostasis, are now understood to actively regulate immune responses, inflammation, and tumour progression. Despite their broad functional repertoire, the molecular mechanisms governing platelet activation and secretion remain incompletely defined. Recent evidence has revealed that platelets contain both the constitutive proteasome and the immunoproteasome, proteolytic complexes previously thought to function primarily in nucleated immune cells. This dissertation investigates how these systems regulate platelet biology and influence platelet-driven immune and tumour interactions.
The clinical relevance of platelet proteasome function was assessed through a meta-analysis of thrombocytopenia in multiple myeloma patients treated with proteasome inhibitors. Proteasome inhibition significantly increased thrombocytopenia incidence, with risk dependent on inhibitor type and dosage, underscoring the hematologic consequences of targeting proteasomal pathways. Mechanistic studies in human platelets revealed substantial interindividual variability in proteasome and immunoproteasome activity, suggesting that proteasomal composition contributes to donor-specific differences in platelet responsiveness. Unlike nucleated cells, platelets do not upregulate immunoproteasome subunits in response to inflammatory stimuli, indicating that their proteasomal profile is established during megakaryopoiesis. Selective inhibition of immunoproteasome catalytic subunits modulated platelet secretion in a subunit-specific manner, enhancing dense-granule release without impairing aggregation. Proteomic analysis of activated platelet supernatants demonstrated altered secretion of proteins linked to metabolic and mitochondrial pathways, implicating the immunoproteasome in the regulation of platelet bioenergetics and intercellular communication.
Importantly, platelets with selectively inhibited immunoproteasome subunits released factors that markedly influenced breast cancer cell behaviour. Inhibition of the β1i subunit promoted migration of triple-negative breast cancer cells, increased angiogenic signalling, and induced markers associated with epithelial-mesenchymal transition. Collectively, this work establishes the platelet immunoproteasome as regulator of platelet secretion and signalling, with implications for immune regulation and tumour progression.
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