Programmed elimination of cells by caspase-independent cell extrusion in C. elegans

The elimination of unnecessary or defective cells from metazoans occurs during normal development and tissue homeostasis as well as in response to infection or cellular damage(1). While many cells are removed through caspase-mediated apoptosis followed by phagocytosis by engulfing cells(2), other mechanisms of cell elimination occur(3), including the extrusion of cells from epithelia via a poorly understood, possibly caspase-independent process(4). Here we identify a mechanism of cell extrusion that is caspase-independent and that can eliminate a subset of the Caenorhabditis elegans cells programmed to die during embryonic development. In wild-type animals, these cells die soon after their generation via caspase-mediated apoptosis. However, in mutants lacking all four C. elegans caspase genes, these cells nonetheless are eliminated by being extruded from the developing embryo into the extra-embryonic space of the egg. The shed cells exhibit apoptosis-like cytological and morphological characteristics, indicating that apoptosis can occur in the absence of caspases in C. elegans. We describe a kinase pathway required for cell extrusion involving PAR-4, STRD-1 and MOP-25.1/2, the C. elegans homologs of the mammalian tumor suppressor kinase LKB1 and its binding partners STRADα and MO25α. The AMPK-related kinase PIG-1, a possible target of the PAR-4:STRD-1:MOP-25 kinase complex, is also required for cell shedding. PIG-1 promotes shed cell detachment by preventing the cell surface expression of cell-adhesion molecules. Our findings reveal a mechanism for apoptotic cell elimination fundamentally distinct from that of canonical programmed cell death.