Caspases: A Molecular Switch Node in the Crosstalk between Autophagy and Apoptosis

Abstract

Autophagy and apoptosis are two important catabolic processes contributing to the maintenance of cellular and tissue homeostasis. Autophagy controls the turnover of protein aggregates and damaged organelles within cells, while apoptosis is the principal mechanism by which unwanted cells are dismantled and eliminated from organisms. Despite marked differences between these two pathways, they are highly interconnected in determining the fate of cells. Intriguingly, caspases, the primary drivers of apoptotic cell death, play a critical role in mediating the complex crosstalk between autophagy and apoptosis. Pro-apoptotic signals can converge to activate caspases to execute apoptotic cell death. In addition, activated caspases can degrade autophagy proteins (i.e., Beclin-1, Atg5, and Atg7) to shut down the autophagic response. Moreover, caspases can convert pro-autophagic proteins into pro-apoptotic proteints to trigger apoptotic cell death instead. It is clear that caspases are important in both apoptosis and autophagy, thus a detailed deciphering of the role of caspases in these two processes is still required to clarify the functional relationship between them. In this article, we provide a current overview of caspases in its interplay between autophagy and apoptosis. We emphasized that defining the role of caspases in autophagy-apoptosis crosstalk will provide a framework for more precise manipulation of these two processes during cell death.

Caspase involvement in autophagy

“…Autophagy and apoptosis are interlocked in an extensive crosstalk with each other, therefore it may not be surprising that many ATGs are recognized and cleaved by caspases [10], [37], [62], [63]. In most cases, interaction of the caspase with the ATG protein leads to abrogation of the autophagic function of the latter, and the homeostatic balance shifts in favor of an apoptotic profile ( Figure 2) [11], [52], [64].…”

“…Main function in Autophagy ULK-complex ULK Initiation Atg1 homologues; Ser/Thr kinases that mediate mTOR signaling and upregulate downstream autophagy mediators [38]- [40] ATG13 Initiation ULK substrate that modulates the activity of the ULK complex [38] FIP200 Initiation Atg17 homologue; ULK substrate that also modulates the activity of the ULK complex [37] ATG101 Initiation Interacts with ULK1 and ATG13 and protects it from degradation [41] PI3K-complex …”

“…Many steps in this cascade are controlled by the interactions of several ATGs with non-autophagy exclusive regulators including caspases [3], [9], [10], [13], [37]. In order to gain a clearer overview of the ways caspases can associate with ATGs and modulate autophagy, we firstly describe the stepwise assembly of the autophagic machinery in mammalian systems.…”

Cytotoxicity of Bothrops pauloensis Venom on Madin-Darby Canine Kidney Cells: Cell Death Mechanism

“…We measured the changes in caspases 3 and 7, key proteases required for apoptosis [11], in MDCK cells. In Figure 3A and 3B, BpV (15 and 25 µg/mL) treatment induced activation of caspase 3 and caspase 7.…”

A matter of regeneration and repair: caspases as the key molecules

“…In addition, autophagy can decrease the inflammatory response by regulating pyroptosis, which is a caspase-1-mediated cell death mechanism (some caspases like caspase-3 mediate the cleavage of important autophagic proteins, like Beclin) and it reduces autophagy in an indirect manner and promotes apoptosis. have an antiautophagic effect that inhibits autophagy, while caspase-3 and caspase-9 have proautophagic effects (Norman et al, 2010;Oral et al, 2012;Tiwari et al, 2014;Wu et al, 2014;Shalini et al, 2015). The roles of the protein-protein interactions between caspases and some proteins such as Atg in caspase-mediated autophagyapoptosis crosstalk are still unclear (Figure 1).…”