[
International Worm Meeting,
2013]
Necrosis is the premature death of cells caused by external factors, such as acute cell injury or trauma. In contrast to apoptosis, the programmed cell death, necrosis is caspase-independent and necrotic cells are morphologically distinct from apoptotic cells. Although these two categories of cell deaths are genetically different, it has been suggested that necrotic cell corpses are actively removed by the same set of genes required in apoptotic cell removal indicating they might share a similar clearance mechanism. In the nematode Caenorhabditis elegans, gain-of-function mutations in certain ion channel subunits result in necrotic-like cell death of six touch neurons. Necrotic touch neurons are subsequently engulfed and degraded inside engulfing cells. However, it is unclear how necrotic cells are recognized by phagocytes. Phosphatidylserine (PS) is an important apoptotic cell surface signal that attracts engulfing cells. Using ectopically expressed MFG-E8, a high-affinity PS-binding protein, we observed that PS was actively present on the surface of necrotic touch neurons. In addition, phagocytic receptor CED-1, whose function is needed for the efficient clearance of apoptotic cells, also acts as a phagocytic receptor for necrotic cells. We demonstrate that necrotic cells, like apoptotic cells, rely on cell-surface PS as an "eat me" signal to attract CED-1. We further found CED-7, the worm homolog of mouse ABC1 transporter, was necessary for PS-exposure on necrotic cell surfaces. Moreover, we discovered another protein contributing to the presentation of PS on necrotic cell surfaces and acting in a parallel pathway to CED-7. Our findings suggest between two distinct cell deaths, a conserved mechanism may exist for the recognition of cell corpse.
Li, Zao, Nagaoka, Yuji, Zhou, Zheng, Morino, Eri, Venegas, Victor, Audhya, Anjon, Raghavan, Prashant, Nakanishi, Yoshinobu
[
International Worm Meeting,
2015]
Necrosis is the premature death of cells caused by cell injury and genetic alternations and is closely related to human diseases including neuron degeneration, stroke, and cancer. Like apoptotic cells, necrotic cell also need to be swiftly removed from the organisms to prevent inflammatory and autoimmune responses. However, unlike apoptosis, the programmed cell death, necrosis is a caspase-independent cellular event and necrotic cells show morphologically distinct features from the button-like apoptotic cells. In the nematode Caenorhabditis elegans, gain-of-function mutations in certain ion channel subunits result in necrotic-like cell death of six touch neurons. Necrotic touch neurons are subsequently engulfed and degraded inside engulfing cells. However, it is unclear of how necrotic cells are recognized by phagocytes. Phosphatidylserine (PS) is an important apoptotic cell surface signal that attracts engulfing cells. Using ectopically expressed MFG-E8, a high-affinity PS-binding protein, we observed that PS was actively present on the surface of necrotic touch neurons. In addition, we found that CED-1, the phagocytic receptor could also recognize necrotic cells by associating with PS. We further found CED-7, the worm homolog of mouse ABC1 transporter, was necessary for PS-exposure on necrotic cell surfaces. In addition to CED-7, ANOH-1, the C. elegans homolog of the mammalian Ca2+-dependent phospholipid scramblase TMEM16F, plays an independent role in promoting PS exposure on necrotic cells. The combined activities from CED-7 and ANOH-1 ensure sufficient exposure of PS on necrotic cells to attract their phagocytes. Our work indicates that cells killed by different mechanisms (necrosis or apoptosis) expose a common "eat me" signal to attract their phagocytic receptor(s); furthermore, unlike what was previously believed, necrotic cells actively present PS on their outer surfaces through two distinct molecular mechanisms rather than leaking out PS passively.