Abstract
We have recently shown that IKK complex plays an important non-genomic role in platelet function, i.e., regulates SNARE machinery-dependent membrane fusion. In this connection, it is well known that MALT1, whose activity is modulated by proteasome, plays an important role in the regulation of IKK complex. Therefore, the present studies investigated the mechanism by which IKK signaling is regulated in the context of the platelet proteasome. It was found that platelets express a functional proteasome, and form CARMA/MALT1/Bcl10 (CBM) complex when activated. Using a pharmacological inhibitor, the proteasome was found to regulate platelet function (aggregation, integrin activation, secretion, phosphatidylserine exposure and changes in intracellular calcium). It was also found to regulate thrombogenesis and physiologic hemostasis. We also observed, upon platelet activation, that MALT1 is ubiquitinated, and this coincides with the activation of the IKK/NF-κB-signaling pathway. Finally, we observed that the proteasome inhibitor blocks CBM complex formation and the interaction of IKKγ and MALT1; abrogates SNARE formation, and the association of MALT1 with TAK1 and TAB2, which are upstream of the CBM complex. Thus, our data demonstrate that MALT1 ubiquitination is critical for the engagement of CBM and IKK complexes, thereby directing platelet signals to the NF-κB pathway.
Highlights
The proteasome is responsible for selective degradation of damaged proteins and short-lived regulatory proteins, which are crucial in many physiological and pathophysiological cellular processes, including cell cycle progression or inflammation[1,2,3,4]
It is to be noted that pharmacological inhibitors of the proteasome have been recently found to influence processes that are known to contribute to the genesis of thrombosis, e.g., they prevent the expression of E-selectin, vascular cell adhesion molecule-1, and P-selectin in activated human endothelial cells[9,10,11]
In terms of the mechanism, we found that MALT1 is associated with the kinases transforming growth factor beta-activated kinase 1 (TAK1) and TAK1 binding protein 2 (TAB2) in stimulated platelets, and that they are upstream of CBM complex formation
Summary
The proteasome is responsible for selective degradation of damaged proteins and short-lived regulatory proteins, which are crucial in many physiological and pathophysiological cellular processes, including cell cycle progression or inflammation[1,2,3,4]. One of the members of the CBM complex, namely MALT1 is known to be ubiquitinated in T/B-cells, which is a key step in regulating the CBM complex formation Such modification affects the scaffolding function of MALT1 thereby promoting the recruitment of IKKγ[23,24,25], phosphorylation and degradation of the inhibitory cytoplasmic NF-κB chaperone (IKKα) by the proteasome; which in turn leads[17, 26] to the activation of the IKK complex[23, 24]. Our findings support the notion that platelets express a functional proteasome system, and suggest that it may serve as a potential target for managing thrombosis-based disease states
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