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.