Apoptosis and necroptosis
Apoptosis is the best characterized form of cell death, which is under molecular control and differs histologically and biochemically from necrosis, an unregulated or accidental cell death (reviewed in (Vanden Berghe, Kaiser, Bertrand, & Vandenabeele, 2015)). Until recently, apoptosis was considered the only form of PCD, however, the discovery of specific inhibitors of necrotic processes together with a systematic biochemical and genetic analysis, have redefined necrosis as a programmed and regulated cell death, also termed necroptosis (reviewed in (Gudipaty et al., 2018; Pasparakis & Vandenabeele, 2015; Vanden Berghe et al., 2015)).
Unlike accidental necrosis which is mainly caused by trauma, necroptosis is a biochemically controlled process activated by receptor interacting proteinkinases-1 and 3 (RIPK1 and RIPK3) and mediated by the mixed lineage kinase domain-like protein (MLKL) (Galluzzi, Kepp, & Kroemer, 2014; Linkermann et al., 2014; Vandenabeele, Galluzzi, Berghe, & Kroemer, 2010). The executioner mechanism of MLKL in necroptosis is not clear; nevertheless, two independent and non-exclusive models have been proposed to explain it. One of them is based on the recruitment of Ca2+ and Na+ ion channels by MLKL once inserted in plasma membrane, causing a massive osmotic imbalance that leads to membrane permeabilization and cell lysis, a distinctive feature of necroptotic cell death (Cai et al., 2014; X. Chen et al., 2014). The other model proposes a pore-forming mechanism by MLKL oligomerization at plasma membrane, which directly induces leaking of intracellular contents and cell lysis (Dondelinger et al., 2014; Su, Yang, Xu, Chen, & Yu, 2015).
Necroptosis could be induced by the proinflammatory cytokine tumor necrosis factor (TNF) under certain cellular conditions, through the signaling cascade of TNF receptor 1 (TNFR1) which lead to the activation of RIP kinases and formation of necrosome complex (reviewed in (Pasparakis & Vandenabeele, 2015)). TNFR1 also activates the apoptotic cascade by the recruitment of cytosolic complexes IIa and IIb, in a mechanism that is regulated by RIPK1 (Silke, Rickard, & Gerlic, 2015). Other membrane receptors that induce necroptosis include FAS (FS-7 associated surface antigen), TRAILR1 and TRAILR2 (TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 and 2), which normally induce apoptosis through the activation of Caspase 8, but could recruit RIPK1 to initiate the formation of the necrosome under Caspase 8 blockade (Bertrand & Vandenabeele, 2011; Feoktistova et al., 2011; Humphries et al., 2015). Interestingly, RIPK1 seems to act as a molecular switch between apoptosis and necroptosis depending on the cellular conditions, a transition that is dynamically regulated by posttranslational modifications and protein expression (Feoktistova et al., 2011; Geng et al., 2017).
Furthermore, these types of PCD can be presented in specific variants, which are triggered by particular events and possess additional biological consequences. For example, anoikis is a special type of apoptosis which is induced by the loss of cell-cell/cell-extracellular matrix (ECM) contacts (Gilmore, 2005; Paoli, Giannoni, & Chiarugi, 2013). When cell is detached from neighboring cells or from the surrounding ECM, the disruption of cadherin or integrin interactions, respectively, triggers a caspase-dependent mechanism that ends in a PCD (Paoli et al., 2013). Selected cells can be also excluded from epithelial layers due to malignant transformation or overcrowding by a process called “extrusion”, resulting in the activation of a biochemical program that eliminates extruded and detached cells by anoikis (Gudipaty et al., 2018). Likewise, regulated or programmed necrosis includes a variety cell death programs with a common cellular phenotype but different molecular pathways.