MALT1-ubiquitination triggers non-genomic NF-κB/IKK signaling upon platelet activation

PloS One
Zubair A KarimFadi T Khasawneh

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 ...Continue Reading

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Citations

Jan 4, 2020·Journal of Thrombosis and Haemostasis : JTH·Lisa ColbergUlrike Seifert
Nov 5, 2016·Journal of Medical Virology·Yi ZhangMengzhou Zhou
Feb 26, 2019·Proceedings of the National Academy of Sciences of the United States of America·Ana Kasirer-FriedeSanford J Shattil
Nov 25, 2017·Mediators of Inflammation·Thomas M VallanceSakthivel Vaiyapuri
Aug 30, 2019·International Journal of Molecular Sciences·Kevin KojokYahye Merhi
Dec 21, 2018·Journal of the American Heart Association·Kevin KojokYahye Merhi
Sep 12, 2019·Biochemistry and Biophysics Reports·Enma V Paez EspinosaFadi T Khasawneh
Feb 16, 2021·Frontiers in Pharmacology·Sisi LingWenchao Ou
May 1, 2021·International Journal of Molecular Sciences·Abed El-Hakim El-Kadiry, Yahye Merhi

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Methods Mentioned

BETA
ubiquitination
flow cytometry
co-IP

Software Mentioned

GraphPad PRISM

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