The crosstalk between autophagy and apoptosis: where does this lead?

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Prot Cell

2012, Vol. 3

Issue (1) : 17-27 https://doi.org/10.1007/s13238-011-1127-x PMID: 22314807

REVIEW

The crosstalk between autophagy and apoptosis: where does this lead?

Claire Gordy, You-Wen He(

)

Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA

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Abstract

Recent advances in the understanding of the molecular processes contributing to autophagy have provided insight into the relationship between autophagy and apoptosis. In contrast to the concept of “autophagic cell death,” accumulating evidence suggests that autophagy serves a largely cytoprotective role in physiologically relevant conditions. The cytoprotective function of autophagy is mediated in many circumstances by negative modulation of apoptosis. Apoptotic signaling, in turn, serves to inhibit autophagy. While the mechanisms mediating the complex counter-regulation of apoptosis and autophagy are not yet fully understood, important points of crosstalk include the interactions between Beclin-1 and Bcl-2/Bcl-xL and between FADD and Atg5, caspase- and calpain-mediated cleavage of autophagy-related proteins, and autophagic degradation of caspases. Continued investigation of these and other means of crosstalk between apoptosis and autophagy is necessary to elucidate the mechanisms controlling the balance between survival and death both under normal conditions and in diseases including cancer.

Keywords autophagy apoptosis Beclin-1 lymphocytes

Corresponding Author(s): He You-Wen,Email:youwen.he@duke.edu

Issue Date: 01 January 2012

Cite this article:

Claire Gordy,You-Wen He. The crosstalk between autophagy and apoptosis: where does this lead?[J]. Prot Cell, 2012, 3(1): 17-27.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-011-1127-x
https://academic.hep.com.cn/pac/EN/Y2012/V3/I1/17

Fig.1 Release of Bcl-2/Bcl-xL-mediated repression of Beclin-1-induced autophagy through disruption of the Bcl-2/Bcl-xL-Beclin-1 interaction.
Under nutrient-sufficient conditions, Beclin-1 is bound by Bcl-2 or Bcl-xL, inhibiting its ability to initiate autophagy. During starvation or other stress conditions, several mechanisms mediate the disruption of this interaction to allow autophagy. These mechanisms include DAPK-mediated phosphorylation of the BH3 domain of Beclin-1, JNK-mediated phosphorylation of the non-structured loop of Bcl-2, competition with Bad and Bax for Bcl-2/Bcl-xL binding, and binding of the DAMP molecule HMGB-1 to Beclin-1.

Fig.2 Mechanisms mediating the mutual negative regulation of autophagy and apoptosis.
Beclin-1 is required for autophagosome initiation and autophagosome closure, while Atg5 is required for autophagosome elongation. The autophagic functions of both of these proteins are negatively regulated by apoptotic signaling. Beclin-1 is cleaved by caspases, and Atg5 is cleaved by calpain-1 and calpain-2. These cleavage events serve not only to inhibit autophagy, but also to enhance apoptosis, as a C-terminal Beclin-1 cleavage product (CT) and an N-terminal Atg5 cleavage product (NT) are each targeted to the mitochondria, where they directly induce the release of cytochrome c. Full-length Beclin-1 and Atg5 oppose this process by mediating the autophagic degradation of active caspase 8.

Fig.3 Crosstalk between the extrinsic apoptotic and autophagic pathways.
Binding of a death receptor to its ligand results in the recruitment of pro-caspase 8 to the DISC through its interaction with the adapter protein FADD. Pro-caspase 8 cleavage results in the relase of active caspase 8, which mediates apoptosis and inhibits autophagy through an unknown mechanism. The caspase 8 inhibitory proteins c-FLIP and v- FLIP interact with Atg3, thereby preventing interaction between Atg3 and LC3 and inhibiting autophagy. The FLIP/Atg3 interaction is inhibited by starvation, allowing autophagy to proceed. Similarly, FADD directly interacts with Atg5; however, this interaction appears to inhibit apoptosis rather than autophagy.

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