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

Abstract

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.

• Authors: Scott McComb, Pik Ki Chan, Anna Guinot, Holmfridur Hartmannsdottir, Silvia Jenni, Maria Pamela Dobay, Jean-Pierre Bourquin, Beat C Bornhauser
• Journal: Science advances (Sci Adv) Vol. 5 Issue 7 Pg. eaau9433 (07 2019) ISSN: 2375-2548 [Electronic] United States
• PMID: 31392262 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytochromes c
• CASP3 protein, human
• Caspase 3
• Caspase 7
• Caspase 8
• Caspase 9

Topics

• Apoptosis (genetics)
• Caspase 3 (genetics)
• Caspase 7 (genetics)
• Caspase 8 (genetics)
• Caspase 9 (genetics)
• Cell Polarity (genetics)
• Cytochromes c (genetics)
• Feedback, Physiological
• Gene Knockout Techniques
• Humans
• Mitochondria (genetics)
• Signal Transduction (genetics)