Fig. 2: Overview of the most prominent cell death modalities described in keratinocytes.

Apoptosis is the primary cell death modality in homeostatic keratinocytes. Intrinsic apoptosis is initiated by activation of the BCL-2 family members BAK and BAX, mediating mitochondrial leakage resulting in cytochrome c release into the cytosol. This event triggers formation of the apoptosome which assembles and activates caspase-9. Subsequently the executioner caspases-3 and -7 are cleaved and activated, mediating cell demise. Extrinsic apoptosis is triggered by binding of toxic agents to death receptors. This results in the assembly of a complex containing adaptor proteins (such as FADD and TRADD) and caspase-8, followed by cleavage of caspase-8 and subsequently of caspase-3 and -7. In conditions where apoptosis is blocked, binding of death receptors can lead to induction of necroptosis. This is mediated by RIPK3 phosphorylation leading to phosphorylation of MLKL, pore formation and cell lysis. Keratinocytes can die by pyroptosis through DAMP or PAMP recognition. Pyroptosis is preceeded by inflammasome formation. In this multi-protein complex, caspase-1 is assembled and cleaved, an event that leads to cleavage of pro-IL-1β and pro-IL-18 into their mature forms and cleavage of GSDMs, inducing pore formation in the plasma membrane and release of cytokines. Ferroptosis is a regulated cell death programme dependent on iron and resulting in lipid peroxidation of the phospholipids present in the plasma membrane by reactive oxygen species (ROS). GPX4 plays a crucial role in protecting cells from ferroptosis and this enzyme depends on cysteine as a co-factor.