A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans

Abstract

Similar to mammalian excitotoxic cell death, necrotic-like cell death (NCD) in Caenorhabditis elegans can be initiated by hyperactive ion channels. Here we investigate the requirements for genes that execute and regulate programmed cell death (PCD) in necrotic-like neuronal death caused by a toxic MEC-4 channel. Neither the kinetics of necrosis onset nor the total number of necrotic corpses generated is altered by any C. elegans mutation known to block PCD, which provides genetic evidence that the activating mechanisms for NCD and apoptotic cell death are distinct. In contrast, all previously reported ced genes required for phagocytotic removal of apoptotic corpses, as well as ced-12, a new engulfment gene we have identified, are required for efficient elimination of corpses generated by distinct necrosis-inducing stimuli. Our results show that a common set of genes acts to eliminate cell corpses irrespective of the mode of cell death, and provide the first identification of the C. elegans genes that are required for orderly removal of necrotic cells. As phagocytotic mechanisms seem to be conserved from nematodes to humans, our findings indicate that injured necrotic cells in higher organisms might also be eliminated before lysis through a controlled process of corpse removal, a hypothesis that has significant therapeutic implications.

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

“…Our results are consistent with findings in the nematode Caenorhabditis elegans, in which a common set of engulfment genes mediates the uptake of both apoptotic and necrotic-like cells (49). Since the phagocytosis process is highly conserved from nematodes to humans, injured necrotic cells in higher organisms may also be at least partially eliminated through a very well-regulated process of dead cell removal largely common for apoptotic and necrotic cells (49).…”

Apaf-1-independent programmed cell death in mouse development

“…In C. elegans, a common set of genes mediates the removal of both apoptotic and necrotic cell corpses. 41 Conversely, different mechanisms have been proposed to clear apoptotic and necrotic cells in mammalian system. 42 Apoptotic cells expose phosphatidylserine, which is recognized by specific receptors or opsonins for engulfment.…”

Noncanonical cell death programs in the nematode Caenorhabditis elegans

“…79 Necrotic neurons may lyse, but more often appear to be removed by phagocytosis before membrane disruption. 79,80 Interestingly, the C. elegans genes involved in phagocytotic removal of apoptotic corpses are also needed for efficient elimination of necrotic corpses, suggesting common recognition and removal mechanisms of apoptotic and necrotic cells. 80 Toxic mec-4(d) mutations encode amino-acid substitutions that increase channel conductance.…”

“…79,80 Interestingly, the C. elegans genes involved in phagocytotic removal of apoptotic corpses are also needed for efficient elimination of necrotic corpses, suggesting common recognition and removal mechanisms of apoptotic and necrotic cells. 80 Toxic mec-4(d) mutations encode amino-acid substitutions that increase channel conductance. 77,[81][82][83] Genetic perturbations of other C. elegans channels, including those that reduce desensitization of the DEG-3 acetylcholine receptor 84,85 and expression of constitutively active Gas 86,87 (thought to induce glutamate excitotoxicity), can also initiate necrosis.…”