Caspase-7 mediates caspase-1-induced apoptosis independently of Bid

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.