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.