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The tyrosine kinase BMX is an essential mediator of inflammatory arthritis in a kinase-independent manner

Gottar-Guillier, Marie, Dodeller, Francis, Huesken, Dieter, Iourgenko, Vadim, Mickanin, Craig, Labow, Mark, Kinzel, Bernd, Mueller, Matthias, Gaveriaux, Samuel, Alitalo, Kari, Littlewood-Evans, Amanda and Cenni, Bruno (2011) The tyrosine kinase BMX is an essential mediator of inflammatory arthritis in a kinase-independent manner. Journal of Immunology, 186 (10). pp. 6014-6023. ISSN 0022-1767


The inflammatory cytokine TNF plays a central role in autoimmune disorders such as rheumatoid arthritis (RA). We identified the tyrosine kinase bone marrow kinase on chromosome X (BMX) as an essential component of the TNF signaling pathway in genome-wide siRNA screens. Transient depletion of BMX strongly reduced secretion of IL-8 in cell lines and primary human cells stimulated by TNF, IL-1β or TLR agonists. BMX was required for full phosphorylation of the p38 MAPK, ERK and JNK. The following epistasis analysis indicated that BMX acts downstream or at the same level as the complex of TGFβ activated kinase 1 (TAK1) and TAK1 binding protein (TAB). At the cellular level, regulation of the IL-8 promoter required the pleckstrin homology (PH) domain of BMX and that could be replaced by an ectopic myristylation signal, indicating a requirement for BMX membrane association. In addition, activation of the IL-8 promoter in vitro required the catalytic activity of BMX. Genetic ablation of BMX conferred protection in the mouse arthritis model of passive K/BxN serum transfer, confirming that BMX is an essential mediator of inflammation in vivo. However, genetic replacement with a catalytically inactive BMX allele was not protective in the same arthritis animal model. We conclude that BMX is an essential component inflammatory cytokine signaling and that catalytic, as well as non-catalytic functions of BMX are involved.

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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15