Figure 12. Schematic model of ER involvement in L-Arg depletion-induced autophagy, survival and apoptosis. (A) This is a schematic outline to portray a plausible mechanism of how L-Arg deprivation induces autophagy via ER stress. Activated ERN1 splices a 26-nucleotide sequence from XBP-1, resulting in a translational frame-shift to generate sXBP1, a potent transcription factor involved in the expression of ER-associated degradation (ERAD) genes, such as ER degradation-enhancing mannosidase-like protein 1 (EDEM1). At the same time, MAPK8 is phosphorylated, allowing the release of BECN1 from the BECN1-BCL2 complex and the generation of the autophagosome. In addition, phosphorylation of EIF2S1 by EIF2AK4, or by EIF2AK3 in the absence of EIF2AK4, induces the expression of genes as ATF4 and other genes involved in the activation of the autophagy pathway. (B) Apoptosis (right) and survival (left) responses triggered by L-Arg depletion are dependent on ER stress and autophagy. Depletion of L-Arg induces an ER stress response that triggers autophagy as a way for survival (left). When autophagy is inhibited, ER stress signals lead to apoptosis (right). See the text for further details.