Interplay between the endoplasmic reticulum, Ca2+ and autophagy induced by various stressors

Autophagy is an evolutionary conserved degradation process responsible for the removal of superfluous or damaged proteins and organelles. Autophagy maintains cellular health during stress conditions like nutrient or growth-factor depletion and is implicated in many diseases like cancer and neurodegeneration. The endoplasmic reticulum (ER), the major organelle for protein and lipid synthesis and for intracellular Ca2+ storage, plays a central role in controlling autophagy. Recently, the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), the main ER Ca2+-release channel, emerged as a major player in the cellular decisions determining cell fate (as autophagy and apoptosis).

Abnormal intracellular conditions can lead to the accumulation of unfolded or misfolded proteins in the ER, a situation known as ER stress. ER stress is also important in various pathologies and is also related to the regulation of ER Ca2+ release via the IP3R. The best known response to ER stress is the unfolded protein response (UPR) which alleviates the accumulation of those proteins via a characteristic set of signaling pathways that reduce protein synthesis, increase chaperone activity and activate degradation of misfolded proteins (2). Importantly, part of this response involves autophagy.

We therefore aim to investigate in detail the molecular mechanisms, regulation and cellular role of the IP3R and Ca2+ in autophagy induced by various means and particularly in ER stress-induced autophagy.