cFLIP L protects macrophages from LPS-induced pyroptosis via inhibition of complex II formation

Macrophages cFLIP out Pathogens have evolved to survive within hosts in part by interfering with host signaling cascades. Yersinia bacteria use the effector protein YopJ to thwart MAP kinase signaling downstream of Toll-like receptor activation. In response to YopJ, host cells can release interleukin-1β and initiate pyroptosis by inhibition of the kinase TAK1 and subsequent caspase-8–directed cleavage of gasdermin D, a protein that forms cell membrane pores. Muendlein et al. report that cFLIP, a major antiapoptotic regulator, plays a central role in this process. Knockdowns of the long but not short cFLIP isoform in macrophages removes the requirement for TAK1 inhibition. Rather, deficiency of the long isoform fuels caspase-8 activation, mitochondrial complex II formation, pyroptosis, and interleukin-1β secretion in response to lipopolysaccharide alone, underscoring its importance for cell death and inflammation. Science , this issue p. 1379