Unconventional cell death programs
In addition to the classical forms of PCD and their emerging
submodalities, other authors are reporting “particular” or
“unconventional” ways in which cells die, involving distinct molecular
events not fully understood yet. In line with this, phagoptosis and
entosis have been described as specific forms of cell death which
implicate the assimilation of a cell by other cell, a phenomenon that
could lead to different outcomes (reviewed in
(Gudipaty et al., 2018)). When a viable
cell is phagocyted by other active live cell it falls undergo a process
called phagoptosis, different from phagocytosis of apoptotic or dead
cells by macrophages. It could be homotypic or heterotypic, if the
fussed cells are of the same or different type, respectively. The
molecular pathway has not been characterized in deep, but it requires
the exposure of phosphatidylserine in cell surface and the loss of CD47,
as occurs with the typical phagocytosis. The physiological importance of
this process includes the turnover of erythrocytes and neutrophils and
it has been described in some pathological conditions such as
neuroinflammation (Gudipaty et al.,
2018). On the other hand, entosis is the opposite process, when a
viable cell invades another life cell, penetrating directly into the
cytoplasm where is vacuolized, turning into an internalized or entosed
cell. An entosed cell could be released resulting in survival, or killed
dying by a lysosomal-dependent degradation that involves LC3 mediated
vacuole targeting, recruitment and fusion. The entotic cell requires
Rho-associated coiled‑coil containing protein kinases (ROCK) activity
and actino-myosin structures that facilitate the cell-into-cell
penetration. This cell death modality is mainly implicated in epithelial
tissue removal and embryo implantation
(Galluzzi et al., 2018).
Some recent studies are also describing other vacuole-dependent forms of
PCD termed as methuosis and paraptosis. The first one involves Ras
hyper‑activation and a massive accumulation of large single membrane
vacuoles full of extracellular fluid which are derived from
macropinosomes. The second variant is associated with cytoplasmic
vacuolization as well, but these vacuoles are derived from expansion of
endoplasmic reticulum and mitochondria. It could be driven by misfolded
protein accumulation or Ca2+ overload and involves
insulin‑like growth factor 1 receptor (IGF1R) activation
(Yan et al., 2020).