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).