Role of IκB Kinase β in Regulating the Remodeling of the CARMA1-Bcl10-MALT1 Complex

Overview

Journal Biochem Biophys Res Commun

Publisher Elsevier

Specialty Biochemistry

Date 2018 Apr 13

PMID 29649481

Citations 1

Authors

Zubair A Karim

Nicole R Hensch

Hanan Qasim

Fatima Z Alshbool

Fadi T Khasawneh

Affiliations

Soon will be listed here.

Abstract

The current work investigates the notion that inducible clustering of signaling mediators of the IKK pathway is important for platelet activation. Thus, while the CARMA1, Bcl10, and MALT1 (CBM) complex is essential for triggering IKK/NF-κB activation upon platelet stimulation, the signals that elicit its formation and downstream effector activation remain elusive. We demonstrate herein that IKKβ is involved in membrane fusion, and serves as a critical protein kinase required for initial formation and the regulation of the CARMA1/MALT1/Bcl10/CBM complex in platelets. We also show that IKKβ regulates these processes via modulation of phosphorylation of Bcl10 and IKKγ polyubiquitination. Collectively, our data demonstrate that IKKβ regulates membrane fusion and the remodeling of the CBM complex formation.

Citing Articles

Regulator of G-Protein Signaling 16 Is a Negative Modulator of Platelet Function and Thrombosis.

Hernandez K, Karim Z, Qasim H, Druey K, Alshbool F, Khasawneh F J Am Heart Assoc. 2019; 8(5):e011273.

PMID: 30791801 PMC: 6474914. DOI: 10.1161/JAHA.118.011273.

References

Mercurio F, Zhu H, Murray B, Shevchenko A, Bennett B, Li J . IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science. 1997; 278(5339):860-6. DOI: 10.1126/science.278.5339.860. View

Schmidt-Supprian M, Courtois G, Tian J, Coyle A, Israel A, Rajewsky K . Mature T cells depend on signaling through the IKK complex. Immunity. 2003; 19(3):377-89. DOI: 10.1016/s1074-7613(03)00237-1. View

Scharschmidt E, Wegener E, Heissmeyer V, Rao A, Krappmann D . Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappa B signaling. Mol Cell Biol. 2004; 24(9):3860-73. PMC: 387748. DOI: 10.1128/MCB.24.9.3860-3873.2004. View

Wei S, Wang H, Zhang G, Lu Y, An X, Ren S . Platelet IκB kinase-β deficiency increases mouse arterial neointima formation via delayed glycoprotein Ibα shedding. Arterioscler Thromb Vasc Biol. 2012; 33(2):241-8. PMC: 3755353. DOI: 10.1161/ATVBAHA.112.300781. View

Woronicz J, Gao X, Cao Z, Rothe M, Goeddel D . IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 1997; 278(5339):866-9. DOI: 10.1126/science.278.5339.866. View

Karim Z, Choi W, Whiteheart S . Primary platelet signaling cascades and integrin-mediated signaling control ADP-ribosylation factor (Arf) 6-GTP levels during platelet activation and aggregation. J Biol Chem. 2008; 283(18):11995-2003. PMC: 2335347. DOI: 10.1074/jbc.M800146200. View

Khoshnan A, Bae D, Tindell C, Nel A . The physical association of protein kinase C theta with a lipid raft-associated inhibitor of kappa B factor kinase (IKK) complex plays a role in the activation of the NF-kappa B cascade by TCR and CD28. J Immunol. 2000; 165(12):6933-40. DOI: 10.4049/jimmunol.165.12.6933. View

Wang D, Matsumoto R, You Y, Che T, Lin X, Gaffen S . CD3/CD28 costimulation-induced NF-kappaB activation is mediated by recruitment of protein kinase C-theta, Bcl10, and IkappaB kinase beta to the immunological synapse through CARMA1. Mol Cell Biol. 2003; 24(1):164-71. PMC: 303359. DOI: 10.1128/MCB.24.1.164-171.2003. View

Regnier C, Song H, Gao X, Goeddel D, Cao Z, Rothe M . Identification and characterization of an IkappaB kinase. Cell. 1997; 90(2):373-83. DOI: 10.1016/s0092-8674(00)80344-x. View

10.

Matsumoto R, Wang D, Blonska M, Li H, Kobayashi M, Pappu B . Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation. Immunity. 2005; 23(6):575-85. DOI: 10.1016/j.immuni.2005.10.007. View

11.

Thome M, Tschopp J . TCR-induced NF-kappaB activation: a crucial role for Carma1, Bcl10 and MALT1. Trends Immunol. 2003; 24(8):419-24. DOI: 10.1016/s1471-4906(03)00177-7. View

12.

Frischbutter S, Gabriel C, Bendfeldt H, Radbruch A, Baumgrass R . Dephosphorylation of Bcl-10 by calcineurin is essential for canonical NF-κB activation in Th cells. Eur J Immunol. 2011; 41(8):2349-57. DOI: 10.1002/eji.201041052. View

13.

Ren Q, Ye S, Whiteheart S . The platelet release reaction: just when you thought platelet secretion was simple. Curr Opin Hematol. 2008; 15(5):537-41. PMC: 2665692. DOI: 10.1097/MOH.0b013e328309ec74. View

14.

Alshbool F, Karim Z, Vemana H, Conlon C, Lin O, Khasawneh F . The regulator of G-protein signaling 18 regulates platelet aggregation, hemostasis and thrombosis. Biochem Biophys Res Commun. 2015; 462(4):378-82. DOI: 10.1016/j.bbrc.2015.04.143. View

15.

Hara H, Bakal C, Wada T, Bouchard D, Rottapel R, Saito T . The molecular adapter Carma1 controls entry of IkappaB kinase into the central immune synapse. J Exp Med. 2004; 200(9):1167-77. PMC: 2211862. DOI: 10.1084/jem.20032246. View

16.

Rothwarf D, Zandi E, Natoli G, Karin M . IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature. 1998; 395(6699):297-300. DOI: 10.1038/26261. View

17.

Hirsh J . Hyperreactive platelets and complications of coronary artery disease. N Engl J Med. 1987; 316(24):1543-4. DOI: 10.1056/NEJM198706113162410. View

18.

Zeng H, Di L, Fu G, Chen Y, Gao X, Xu L . Phosphorylation of Bcl10 negatively regulates T-cell receptor-mediated NF-kappaB activation. Mol Cell Biol. 2007; 27(14):5235-45. PMC: 1951946. DOI: 10.1128/MCB.01645-06. View

19.

Wu C, Ashwell J . NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation. Proc Natl Acad Sci U S A. 2008; 105(8):3023-8. PMC: 2268578. DOI: 10.1073/pnas.0712313105. View

20.

Malaver E, Romaniuk M, DAtri L, Pozner R, Negrotto S, Benzadon R . NF-kappaB inhibitors impair platelet activation responses. J Thromb Haemost. 2009; 7(8):1333-43. DOI: 10.1111/j.1538-7836.2009.03492.x. View