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Cell death triggered by Yersinia enterocolitica identifies processing of the proinflammatory signal adapter MyD88 as a general event in the execution of apoptosis.

Authors
  • Novikova, Lena
  • Czymmeck, Nicole
  • Deuretzbacher, Anne
  • Buck, Friedrich
  • Richter, Kathleen
  • Weber, Alexander N R
  • Aepfelbacher, Martin
  • Ruckdeschel, Klaus
Type
Published Article
Journal
The Journal of Immunology
Publisher
The American Association of Immunologists
Publication Date
Feb 01, 2014
Volume
192
Issue
3
Pages
1209–1219
Identifiers
DOI: 10.4049/jimmunol.1203464
PMID: 24363429
Source
Medline
License
Unknown

Abstract

Many pathogenic microorganisms have evolved tactics to modulate host cell death or survival pathways for establishing infection. The enteropathogenic bacterium Yersinia enterocolitica deactivates TLR-induced signaling pathways, which triggers apoptosis in macrophages. In this article, we show that Yersinia-induced apoptosis of human macrophages involves caspase-dependent cleavage of the TLR adapter protein MyD88. MyD88 was also cleaved when apoptosis was mediated by overexpression of the Toll-IL-1R domain-containing adapter inducing IFN-β in epithelial cells. The caspase-processing site was mapped to aspartate-135 in the central region of MyD88. MyD88 is consequently split by caspases in two fragments, one harboring the death domain and the other the Toll-IL-1R domain. Caspase-3 was identified as the protease that conferred the cleavage of MyD88 in in vitro caspase assays. In line with a broad role of caspase-3 in the execution of apoptosis, the processing of MyD88 was not restricted to Yersinia infection and to proapoptotic Toll-IL-1R domain-containing adapter inducing IFN-β signaling, but was also triggered by staurosporine treatment. The cleavage of MyD88 therefore seems to be a common event in the advanced stages of apoptosis, when caspase-3 is active. We propose that the processing of MyD88 disrupts its scaffolding function and uncouples the activation of TLR and IL-1Rs from the initiation of proinflammatory signaling events. The disruption of MyD88 may consequently render dying cells less sensitive to proinflammatory stimuli in the execution phase of apoptosis. The cleavage of MyD88 could therefore be a means of conferring immunogenic tolerance to apoptotic cells to ensure silent, noninflammatory cell demise.

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