title: 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.affiliation: Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, 20246 Hamburg, Germany;
authors.forename: Lena
authors.initials: L
authors.lastname: Novikova
authors.forename: Nicole
authors.initials: N
authors.lastname: Czymmeck
authors.forename: Anne
authors.initials: A
authors.lastname: Deuretzbacher
authors.forename: Friedrich
authors.initials: F
authors.lastname: Buck
authors.forename: Kathleen
authors.initials: K
authors.lastname: Richter
authors.forename: Alexander N R
authors.initials: AN
authors.lastname: Weber
authors.forename: Martin
authors.initials: M
authors.lastname: Aepfelbacher
authors.forename: Klaus
authors.initials: K
authors.lastname: Ruckdeschel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D017472:Receptors, Interleukin-1 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D016415:Sequence Alignment; D013045:Species Specificity; D051193:Toll-Like Receptors / Q000502:physiology; D015008:Yersinia enterocolitica / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053148:Caspase 3; D016899:Interferon-beta; D053592:Interleukin-1 Receptor-Associated Kinases; D020930:MAP Kinase Kinase Kinases; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; D051193:Toll-Like Receptors; D000099151:MAP Kinase Kinase Kinase 7; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C434984:TIRAP protein, human; C507773:IRAK4 protein, human; C505407:CASP3 protein, human