Abstract
During programmed cell death, apoptotic cells are recognized and rapidly engulfed by phagocytes. Although a number of genes have been identified that promote cell corpse engulfment, it is not well understood how phagocytosis of apoptotic cells is negatively regulated. Here we have identified Caenorhabditis elegans myotubularin MTM-1 as a negative regulator of cell corpse engulfment. Myotubularins (MTMs) constitute a large, highly conserved family of lipid phosphatases. MTM gene mutations are associated with various human diseases, but the cellular functions of MTM proteins are not clearly defined. We found that inactivation of MTM-1 caused significant reduction in cell corpses in strong loss-of-function mutants of ced-1, ced-6, ced-7, and ced-2, but not in animals deficient in the ced-5, ced-12, or ced-10 genes. In contrast, overexpression of MTM-1 resulted in accumulation of cell corpses. This effect is dependent on the lipid phosphatase activity of MTM-1. We show that loss of mtm-1 function accelerates the clearance of cell corpses by promoting their internalization. Importantly, the reduction of cell corpses caused by mtm-1 RNAi not only requires the activities of CED-5, CED-12, and CED-10, but also needs the functions of the phosphatidylinositol 3-kinases (PI3Ks) VPS-34 and PIKI-1. We found that MTM-1 localizes to the plasma membrane in several known engulfing cell types and may modulate the level of phosphatidylinositol 3-phosphate (PtdIns(3)P) in vivo. We propose that MTM-1 negatively regulates cell corpse engulfment through the CED-5/CED-12/CED-10 module by dephosphorylating PtdIns(3)P on the plasma membrane.
Highlights
Phagocytosis of apoptotic cells is essential for animal development, tissue homeostasis and regulation of immune responses
We found that MTM-1. Myotubularins (MTMs)-1 inhibits cell corpse engulfment through a series of evolutionarily conserved signaling molecules (the bipartite GEF (CED-5/DOCK180-CED-12/ ELMO) and the GTPase CED-10/Rac)
We propose that MTM-1 acts through Rac GTPase CED-10 by dephosphorylating the lipid PtdIns(3)P on the plasma membrane
Summary
Phagocytosis of apoptotic cells is essential for animal development, tissue homeostasis and regulation of immune responses. Several evolutionarily conserved intracellular signaling molecules, CED-2/CrkII, CED5/Dock180 and CED-12/ELMO, act downstream of PSR-1, the C. elegans homologue of the human phosphatidylserine receptor. These signaling molecules mediate activation of the small GTPase CED-10/Rac, leading to rearrangement of the actin cytoskeleton which is needed for cell corpse engulfment [6,7,8,9,10,11,12]. No defect in cell corpse engulfment was observed in animals which completely lose the activity of either mig-2 or unc-73 or both, indicating that more complex regulatory mechanisms are involved in CED-10/Rac activation. As earlier studies mainly focused only on positive regulation of engulfment, it is less well understood whether any negative regulatory mechanism is involved
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