Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates
Authors:Steve Brunette1,#, Anupam Sharma1,2,#, Ryan Bell1, Lawrence Puente1 and Lynn A Megeney1,2,3,*
doi: 10.15698/mic2023.08.801
Volume 10, pp. 157 to 169, published 10/07/2023.
1 Regenerative Medicine Program, Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.
2 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
3 Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
# These authors contributed equally to the study.
Keywords:
caspase, metacaspase, yeast, TDP43, proteostasis, protein aggregation.
Corresponding Author(s):
Conflict of interest statement:
The authors declare that the study was carried out with-out any affiliations with commercial or financial entities that could be interpreted as a potential conflict of interest.
Please cite this article as:
Steve Brunette, Anupam Sharma, Ryan Bell, Lawrence Puente and Lynn A Megeney (2023). Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates. Microbial Cell 10(8): 157-169. doi: 10.15698/mic2023.08.801
© 2023 Brunette et al.. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Caspase 3 activation is a hallmark of cell death and there is a strong correlation between elevated protease activity and evolving pathology in neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS). At the cellular level, ALS is characterized by protein aggregates and inclusions, comprising the RNA binding protein TDP-43, which are hypothesized to trigger pathogenic activation of caspase 3. However, a growing body of evidence indicates this protease is essential for ensuring cell viability during growth, differentiation and adaptation to stress. Here, we explored whether caspase 3 acts to disperse toxic protein aggregates, a proteostasis activity first ascribed to the distantly related yeast metacaspase ScMCA1. We demonstrate that human caspase 3 can functionally substitute for the ScMCA1 and limit protein aggregation in yeast, including TDP-43 inclusions. Proteomic analysis revealed that disrupting caspase 3 in the same yeast substitution model resulted in detrimental TDP-43/mitochondrial protein associations. Similarly, suppression of caspase 3, in either murine or human skeletal muscle cells, led to accumulation of TDP-43 aggregates and impaired mitochondrial function. These results suggest that caspase 3 is not inherently pathogenic, but may act as a compensatory proteostasis factor, to limit TDP-43 protein inclusions and protect organelle function in aggregation related degenerative disease.