Figure 8.

Proposed mechanisms for the induction of photoreceptor cell death by atRAL-mediated activation of GSDME. In photoreceptor cells, atRAL stimulates JNK activation, which is at least partially mediated by ROS production, thereby causing damage to the mitochondria (6). Rupture of the mitochondria releases Cyt c into the cytosol, where it promotes the formation of apoptosomes consisting of Cyt c, Apaf-1, and caspase-9 (14). Active caspase-9 cleaves and activates caspase-3, leading to caspase-dependent apoptosis. Alternatively, active caspase-3 cleaves GSDME to generate GSDME-N, which forms aggregates and pores in the plasma membrane and then drives pyroptosis. Rupture of the plasma membrane during pyroptosis results in the leakage of intracellular components, such as HMGB1. In addition, GSDME-N moves to the mitochondria, where it aggregates and permeabilizes mitochondrial membranes, thus aggravating pyroptosis and apoptosis by accentuating Cyt c release and caspase-3 activation. atRAL, all-trans-retinal; Cyt c, cytochrome c; GSDME, gasdermin E; GSDME-N, N-terminal fragment of GSDME; HMGB1, high-mobility group box 1; JNK, c-Jun N-terminal kinase; ROS, reactive oxygen species.