LAUSR

Inflammasomes are innate immune mechanisms that activate caspase‐1 in response to a variety of stimuli, including Salmonella infection. Active caspase‐1 has a potential to induce two different types of cell death, depending on the expression of the pyroptosis mediator gasdermin D (GSDMD); following caspase‐1 activation, GSDMD‐sufficient and GSDMD‐null/low cells undergo pyroptosis and apoptosis, respectively. Although Bid, a caspase‐1 substrate, plays a critical role in caspase‐1 induction of apoptosis in GSDMD‐null/low cells, an additional mechanism that mediates this cell death independently of Bid has also been suggested. This study investigated the Bid‐independent pathway of caspase‐1‐induced apoptosis. Caspase‐1 has been reported to process caspase‐6 and caspase‐7. Silencing of caspase‐7, but not caspase‐6, significantly reduced the activation of caspase‐3 induced by caspase‐1, which was activated by chemical dimerization, in GSDMD/Bid‐deficient cells. CRISPR/Cas9‐mediated depletion of caspase‐7 had the same effect on the caspase‐3 activation. Moreover, in the absence of GSDMD and Bid, caspase‐7 depletion reduced apoptosis induced by caspase‐1 activation. Caspase‐7 was activated following caspase‐1 activation independently of caspase‐3, suggesting that caspase‐7 acts downstream of caspase‐1 and upstream of caspase‐3. Salmonella induced the activation of caspase‐3 in GSDMD‐deficient macrophages, which relied partly on Bid and largely on caspase‐1. The caspase‐3 activation and apoptotic morphological changes seen in Salmonella‐infected GSDMD/Bid‐deficient macrophages were attenuated by caspase‐7 knockdown. These results suggest that in addition to Bid, caspase‐7 can also mediate caspase‐1‐induced apoptosis and provide mechanistic insights into inflammasome‐associated cell death that is one major effector mechanism of inflammasomes.