Life in the balance - a mechanistic view of the crosstalk between autophagy and apoptosis

Cellular stress triggers a fascinating decision-making process in cells; they can either attempt to survive until the stress is resolved through the activation of cytoprotective pathways, such as autophagy, or can commit suicide by apoptosis in order to prevent further damage to surrounding healthy cells. Although autophagy and apoptosis constitute distinct cellular processes with often opposing outcomes, their signalling pathways are extensively interconnected through various mechanisms of crosstalk. The physiological relevance of the autophagy-apoptosis crosstalk is not well understood, but it is presumed to facilitate a controlled and well-balanced cellular response to a given stress signal. In this Commentary, we explore the various mechanisms by which autophagy and apoptosis regulate each other, and define general paradigms of crosstalk on the basis of mechanistic features. One paradigm relates to physical and functional interactions between pairs of specific apoptotic and autophagic proteins. In a second mechanistic paradigm, the apoptosis or autophagy processes (as opposed to individual proteins) regulate each other through induced caspase and autolysosomal activity, respectively. In a third paradigm unique to autophagy, caspases are recruited and activated on autophagosomal membranes. These mechanistic paradigms are discernible experimentally, and can therefore be used as a practical guide for the interpretation of experimental data.