Following sensing of microbial pathogens in the cytosol, the inflammasome mediates the proteolytic activation of pro-inflammatory caspases, the processing of interleukin-1β (IL-1β) and IL-18, and the cleavage of gasdermin D, which leads to the formation of membrane pores and a form of programmed cell death termed pyroptosis. Pathogens manipulate and evade host inflammasome-mediated immune responses, but the underlying mechanisms are not well understood. Mycobacterium tuberculosis has developed intracellular survival strategies to evade host immunity, such as the secretion of eukaryotic-like effectors, but their host targets and roles in host–pathogen interactions remain mostly elusive. Now, Chai, Yu, Zhong et al. identify the M. tuberculosis effector protein PtpB and show that it counteracts gasdermin D-mediated pyroptosis and inflammatory cytokine release by altering the phospholipid composition of the host membrane.
Further experiments showed that PtpB does not inhibit inflammasome assembly, but that the effector targets gasdermin D: infection with a ptpB deletion mutant resulted in lower intracellular amounts of mature IL-1β, caspase 1 and the C-terminal cleavage fragment of gasdermin D, whereas the amounts of these molecules were increased in the supernatant compared with the wild-type. Moreover, deletion of ptpB led to increased intracellular amounts of the N-terminal fragment of gasdermin D, which is the functional domain of gasdermin D that binds to the cell membrane and mediates cytokine release and pyroptosis by pore formation. The results suggest that PtpB inhibits gasdermin D-dependent cytokine release and pyroptosis. In agreement with this, deletion of ptpB increased the secretion of mature IL-1β, caspase 1 and the C-terminal fragment of gasdermin D in wild-type bone marrow-derived macrophages, and increased the proportion of cells with swelling bubbles (a marker of pyroptosis). Importantly, these effects were abolished in cells lacking gasdermin D.
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