Editors' ChoiceCell death

Elimination by Extrusion

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Science Signaling  14 Aug 2012:
Vol. 5, Issue 237, pp. ec215
DOI: 10.1126/scisignal.2003490

Elimination of extra, damaged, or dysfunctional cells is critical to organismal survival. Therefore, cells have multiple routes to achieve programmed cell death. When one of the main routes, caspase-mediated apoptosis, is compromised, limited cell death still occurs in the model organism Caenorhabditis elegans. Denning et al. explored this alternative cell death pathway that resulted in the shedding of ~6 cells from the developing embryo deficient in caspase-mediated apoptosis. By screening for mutants that enabled the survival of one of the cells normally shed in the animals with compromised caspase-mediated apoptosis, the authors identified loss of pig-1 as resulting in animals with an extra (albeit dysfunctional) excretory cell and an extra RME neuron. In addition, pig-1 deficiency reduced the total number of shed cells. PIG-1 is a homolog of MELK, which is related to AMP-regulated kinase (AMPK) and, in mammals, AMPK is activated by phosphorylation by a kinase complex including the kinase LKB1, STRADα, and MO25α. C. elegans deficient in caspase-mediated apoptosis and in which the LKB1 or STRADα homolog were inactivated, or animals in which two of the three MO25α homologs were inactivated, exhibited the extra excretory cell phenotype of the pig-1–deficient animals. The surface abundance of various adhesion proteins (tagged with green fluorescent protein) was reduced in cells that were shed in the animals deficient for caspase-mediated apoptosis; however, when pig-1 was inactivated in these animals, the cell that produced the extra excretory cell had adhesion proteins at the cell surface. In the animals deficient for caspase-mediated apoptosis, inactivation of genes encoding ARF guanosine triphosphatases implicated in endocytosis resulted in the extra excretory cell phenotypes like that of the pig-1 animals. Thus, the authors proposed that activation of an AMPK-related kinase by the LKB1 complex promotes the endocytosis of adhesion proteins to enable a caspase-independent cell shedding pathway that eliminates extra cells in developing C. elegans. This pathway may be important in mammals, because in humans, mutations in LKB1 cause a syndrome associated with intestinal polyps, which may result from defective extrusion of cells from the intestinal epithelia.

D. P. Denning, V. Hatch, H. R. Horvitz, Programmed elimination of cells by caspase-independent cell extrusion in C. elegans. Nature 488, 226–230 (2012). [PubMed]

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