Abstract
Apoptosis ensures removal of damaged cells and helps shape organs during development by removing excessive cells. To prevent the intracellular content of the apoptotic cells causing damage to surrounding cells, apoptotic cells are quickly cleared by engulfment. Tight regulation of apoptosis and engulfment is needed to prevent several pathologies such as cancer, neurodegenerative and autoimmune diseases. There is increasing evidence that the engulfment machinery can regulate the execution of apoptosis. However, the underlying molecular mechanisms are poorly understood. We show that dynein mediates cell non-autonomous cross-talk between the engulfment and apoptotic programs in the Caenorhabditis elegans germline. Dynein is an ATP-powered microtubule-based molecular motor, built from several subunits. Dynein has many diverse functions including transport of cargo around the cell. We show that both dynein light chain 1 (DLC-1) and dynein heavy chain 1 (DHC-1) localize to the nuclear membrane inside apoptotic germ cells in C. elegans. Strikingly, lack of either DLC-1 or DHC-1 at the nuclear membrane inhibits physiological apoptosis specifically in mutants defective in engulfment. This suggests that a cell fate determining dialogue takes place between engulfing somatic sheath cells and apoptotic germ cells. The underlying mechanism involves the core apoptotic protein CED-4/Apaf1, as we find that DLC-1 and the engulfment protein CED-6/GULP are required for the localization of CED-4 to the nuclear membrane of germ cells. A better understanding of the communication between the engulfment machinery and the apoptotic program is essential for identifying novel therapeutic targets in diseases caused by inappropriate engulfment or apoptosis.
Highlights
Dysregulation of apoptosis and engulfment contributes to the etiology of pathologies such as cancer, neurodegenerative and autoimmune diseases[1,2,3,4,5,6]
In ced-3 mutants, we found no DIC positive corpses nor any germ cells marked with dynein light chain 1 (DLC-1)::GFP, demonstrating that DLC-1::GFP accumulation marks apoptotic cells (Fig. 1b)
We investigated the effect of the DLC-1::GFP transgene in gla-3(ok2684) mutants and worms treated with RNAi against the cytoplasmic polyadenylation-element-binding-protein-1 (CPEB1) homolog cbp-3 as these have elevated apoptosis but normal engulfment[37,39]
Summary
Dysregulation of apoptosis and engulfment contributes to the etiology of pathologies such as cancer, neurodegenerative and autoimmune diseases[1,2,3,4,5,6]. Official journal of the Cell Death Differentiation Association. Harders et al Cell Death and Disease (2018)9:1012 accumulation increases at the nuclear membrane[20,21]. Apoptosis culminates in engulfment and degradation of the apoptotic cell. In C. elegans, dead cells are engulfed and degraded by neighboring cells, such as the sheath cells in the germline[22]. The engulfment pathways cooperate with the apoptotic machinery to induce developmental apoptosis, since overactivation of engulfment causes more cells to die[24], while a defect in engulfment causes more cells to survive under limited caspase activity[25,26,27,28,29]. Little is known about the interaction between engulfment and the apoptotic machinery
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