Role of the inositol 1,4,5-trisphosphate receptor/Ca2+-release channel in autophagy

Autophagy is the name for a group of lysosomal degradation processes conserved throughout evolution [1,2]. It is responsible for the disposal of cellular material that cannot be degraded by the ubiquitin-proteasome system, like long-lived proteins, other macromolecules and even entire organelles. Depending on the delivery mechanism of this material to the lysosomes, autophagy is divided into three main types: microautophagy, chaperone-mediated autophagy and macroautophagy [2,3].The latter is the best-studied form of autophagy and involves the formation of a typical double-membrane cistern, named phagophore, which surrounds and ultimately engulfs the cytoplasmic material to be degraded. The resulting vesicle is the autophagosome, which can fuse with late endosomes or lysosomes, leading to the breakdown of its content [1,4]. Because macroautophagy is the main focus of this review, it will further be referred to as autophagy.Appropriate autophagy levels are not only needed for cellular homeostasis (removing of aggregated proteins and damaged organelles) [5,6] but also for development, cell differentiation, ageing and tumor suppression [1,6,7].Depending on the type of stress faced by cells, autophagy can either provide the cell with building blocks and energy (e.g. during starvation) or help the cell to cope with potentially damaging elements (e.g. aggregated proteins, viral infection and other intracellular pathogens) [1,4,6,8,9]. Thus, autophagy ensures cell survival, but if the stress persists for a longer time, it can lead to cell death, also termed programmed cell death type 2 [10]. Cell death is however not the normal outcome of autophagy, and the concept has been proposed that cell death may occur along with autophagy rather than executed by autophagy [11,12].Impaired or altered autophagic flux has been implicated in several pathologies, including cancer and neurodegenerative disorders [1,6,8].In order to avoid uncontrolled or excessive levels of autophagy, the p