Chan, F. H. M., Yeap, H. W., Liu, Z., Rosli, S. N., Low, K. E., Bonne, I., Wu, Y., Chong, S. Z., & Chen, K. W. (2025). Plasticity of cell death pathways ensures GSDMD activation during Yersinia pseudotuberculosis infection. Cell Reports, 44(1), 115216. https://doi.org/10.1016/j.celrep.2024.115216
Abstract:
Macrophages express pattern recognition and cytokine receptors that mediate proinflammatory signal transduction pathways to combat microbial infection. To retaliate against such responses, pathogenic microorganisms have evolved multiple strategies to impede innate immune signaling. Recent studies demonstrated that YopJ suppression of TAK1 signaling during Yersinia pseudotuberculosis infection promotes the assembly of a RIPK1-dependent death-inducing complex that enables caspase-8 to directly cleave and activate gasdermin D (GSDMD). However, whether and how macrophages respond to Yersinia infection in the absence of YopJ or caspase-8 activity remains unclear. Here, we demonstrate that loss of YopJ or its catalytic activity triggers non-canonical inflammasome activation in macrophages and that caspase-11 is required to restrict the bacterial burden in vivo. Under conditions of low caspase-8 activity, wild-type Y. pseudotuberculosis invades macrophages and accesses the cytosol, leading to non-canonical inflammasome activation. Thus, our study highlights the plasticity of death pathways to ensure GSDMD activation during Yersinia infection.
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Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Funding Info:
This research / project is supported by the National Medical Research Council - Open Fund - Individual Research Grant
Grant Reference no. : MOH-001219-00
This research / project is supported by the Ministry of Education - Postgraduate Research Scholarship
Grant Reference no. : NA
This research / project is supported by the NUS Yong Loo Lin School of Medicine - Postgraduate Research Scholarship
Grant Reference no. : NA
This research / project is supported by the National University Health System - Start-up Grant
Grant Reference no. : NUHSRO/2020/117/STARTUP/04
This research / project is supported by the Ministry of Education - NA
Grant Reference no. : MOE-000343-00