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

TY - JOUR

T1 - Cell death triggered by Yersinia enterocolitica identifies processing of the proinflammatory signal adapter MyD88 as a general event in the execution of apoptosis

AU - Novikova, Lena

AU - Czymmeck, Nicole

AU - Deuretzbacher, Anne

AU - Buck, Friedrich

AU - Richter, Kathleen

AU - Weber, Alexander N R

AU - Aepfelbacher, Martin

AU - Ruckdeschel, Klaus

PY - 2014/2/1

Y1 - 2014/2/1

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Apoptosis

KW - Caspase 3

KW - Epithelial Cells

KW - HEK293 Cells

KW - Host-Pathogen Interactions

KW - Humans

KW - Interferon-beta

KW - Interleukin-1 Receptor-Associated Kinases

KW - MAP Kinase Kinase Kinases

KW - Macrophages

KW - Membrane Glycoproteins

KW - Mice

KW - Molecular Sequence Data

KW - Myeloid Differentiation Factor 88

KW - NF-kappa B

KW - Phosphorylation

KW - Protein Processing, Post-Translational

KW - Protein Structure, Tertiary

KW - Receptors, Interleukin-1

KW - Recombinant Fusion Proteins

KW - Sequence Alignment

KW - Species Specificity

KW - Toll-Like Receptors

KW - Yersinia enterocolitica

U2 - 10.4049/jimmunol.1203464

DO - 10.4049/jimmunol.1203464

M3 - SCORING: Journal article

C2 - 24363429

VL - 192

SP - 1209

EP - 1219

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 3

ER -