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

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.

• Authors: Lena Novikova, Nicole Czymmeck, Anne Deuretzbacher, Friedrich Buck, Kathleen Richter, Alexander N R Weber, Martin Aepfelbacher, Klaus Ruckdeschel
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 3 Pg. 1209-19 (Feb 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24363429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MYD88 protein, human
• Membrane Glycoproteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NF-kappa B
• Receptors, Interleukin-1
• Recombinant Fusion Proteins
• TIRAP protein, human
• Toll-Like Receptors
• Interferon-beta
• IRAK4 protein, human
• Interleukin-1 Receptor-Associated Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• CASP3 protein, human
• Caspase 3

Topics

• Amino Acid Sequence
• Animals
• Apoptosis (physiology)
• Caspase 3 (metabolism)
• Epithelial Cells (metabolism)
• HEK293 Cells
• Host-Pathogen Interactions (physiology)
• Humans
• Interferon-beta (immunology)
• Interleukin-1 Receptor-Associated Kinases (metabolism)
• MAP Kinase Kinase Kinases (metabolism)
• Macrophages (immunology, microbiology)
• Membrane Glycoproteins (physiology)
• Mice
• Molecular Sequence Data
• Myeloid Differentiation Factor 88 (chemistry, deficiency, physiology)
• NF-kappa B (metabolism)
• Phosphorylation
• Protein Processing, Post-Translational
• Protein Structure, Tertiary
• Receptors, Interleukin-1 (physiology)
• Recombinant Fusion Proteins (immunology)
• Sequence Alignment
• Species Specificity
• Toll-Like Receptors (physiology)
• Yersinia enterocolitica (physiology)