Structure and function of the ubiquitin‐proteasome system in platelets

Abstract

Platelets are small anucleate blood cells with a life span of 7 to 10 days. They are main regulators of hemostasis. Balanced platelet activity is crucial to prevent bleeding or occlusive thrombus formation. Growing evidence supports that platelets also participate in immune reactions, and interaction between platelets and leukocytes contributes to both thrombosis and inflammation. The ubiquitin‐proteasome system (UPS) plays a key role in maintaining cellular protein homeostasis by its ability to degrade non‐functional self‐, foreign, or short‐lived regulatory proteins. Platelets express standard and immunoproteasomes. Inhibition of the proteasome impairs platelet production and platelet function. Platelets also express major histocompatibility complex (MHC) class I molecules. Peptide fragments released by proteasomes can bind to MHC class I, which makes it also likely that platelets can activate epitope specific cytotoxic T lymphocytes (CTLs). In this review, we focus on current knowledge on the significance of the proteasome for the functions of platelets as critical regulators of hemostasis as well as modulators of the immune response.

Innate immune receptors in platelets and platelet-leukocyte interactions

“…Platelets interact with B‐cells through CD40L‐CD40 participating in Ab isotype switch, and with T cells increasing the frequency of IFN‐γ‐expressing Th1 subset 149 . Importantly, platelets have the necessary machinery for Ag presentation, including immunoproteasome, β2‐microglobulin, and all human leukocyte Ags (HLA) (or MHC in mice) class I subunits 151–153 . Platelets also express the co‐stimulatory molecules CD86, CD40, and ICOSL, being able to present Ags to T lymphocytes inducing both IL‐2 and IFN‐γ secretion and CD69 and IL‐2R expression 154 …”

“…149 Importantly, platelets have the necessary machinery for Ag presentation, including immunoproteasome, 2-microglobulin, and all human leukocyte Ags (HLA) (or MHC in mice) class I subunits. [151][152][153] Platelets also express the costimulatory molecules CD86, CD40, and ICOSL, being able to present Ags to T lymphocytes inducing both IL-2 and IFN-secretion and CD69…”

Proteomics: A Tool to Study Platelet Function

“…Lately, it was shown that platelets acquired all machinery for antigen-presenting through megakaryocytes [ 63 ]. Even though megakaryocytes are found to express both MHC class I and II molecules, the platelets proteome and experimental evidence show only active MHC class I presentation [ 59 , 63 , 64 ]. Interestingly, the declined level of MHC class I molecules on the surface could indicate platelet aging [ 65 ].…”

“…An additional layer in platelet regulation is the ubiquitin-proteasome system, which maintains cellular protein homeostasis, regulates signal transduction cascades, and supplies MHC class I molecules with peptides for antigen presentation [ 64 ]. Platelets express standard and immunoproteasome subunits and display three protease activities, caspase-like, trypsin-like, and chymotrypsin-like activity, executed by the catalytically active β subunits [ 64 , 160 ]. To undergo proteasome degradation, proteins first need to be marked by ubiquitination, a PTM where a small, highly conserved protein called ubiquitin (Ub) is covalently bonded to a lysine residue.…”

The Immune Nature of Platelets Revisited

“…Platelets are estimated to harbor approximately 80,000 MHC-I molecules on their surface [ 92 ], however, there are controversies regarding the functionality and origin of these molecules on platelets [ 93 ]. Nonetheless, it is now known that platelets (and MK) contain all the molecules necessary for antigen processing and presentation to CD8+ T-cells including a complete proteasome [ 149 , 150 ] and co-stimulatory molecules [ 151 , 152 ]. Although the platelet’s surface contains mainly denatured MHC-I molecules, intracellularly, platelets have a large pool of fully intact functional MHC-I molecules that are expressed upon activation.…”