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.

Analysis of differentially expressed proteins in Yersinia enterocolitica-infected HeLa cells

“…3B). Inducing cell death is a common tactic used by bacterial pathogens for effective spread in the host, and Yersinia is not an exception [54]. It would be interesting to establish whether Yersinia promotes cell death in epithelial cells by targeting any of the identified molecules specifically.…”

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

“…While induction of cell death often depends on the balance between proapoptotic and prosurvival signals [68], the exact signaling networks that induce cell survival or cell death after engagement of TLRs are not yet completely understood [69]. There is increasing evidence that the strength, timing, and duration of TLR signaling can significantly modulate downstream outcomes [70], just as previously observed for T-cell receptor signaling [71,72], and more recently for B-cell receptor signaling [73].…”

Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis

“…10 Of note, Yersinia enterocolitica is able to deactivate TLR-induced signaling pathways, by cleaving Myd88, triggering apoptosis in macrophages. 11 This mechanism may increase Yersinia virulence in immunocompetent hosts also. In a recent article by von Bernuth et al, 12 MyD88-deficient mice were found to be susceptible to almost nearly all the microbes tested, including bacteria, viruses, protozoa, and fungi, highlighting the importance of TLR in the immune response to different pathogens.…”