Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7

• Published in: Science advances Vol. 5; no. 7; p. eaau9433
• Main Authors: McComb, Scott, Chan, Pik Ki, Guinot, Anna, Hartmannsdottir, Holmfridur, Jenni, Silvia, Dobay, Maria Pamela, Bourquin, Jean-Pierre, Bornhauser, Beat C
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.07.2019
• Subjects: Apoptosis - genetics; Caspase 3 - genetics; Caspase 7 - genetics; Caspase 8 - genetics; Caspase 9 - genetics; Cell Biology; Cell Polarity - genetics; Cytochromes c - genetics; Feedback, Physiological; Gene Knockout Techniques; Humans; Mitochondria - genetics; SciAdv r-articles; Signal Transduction - genetics
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aau9433

NRC publication: No
Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondrial depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.