A river runs through it: how autophagy, senescence, and phagocytosis could be linked to phospholipase D by Wnt signaling.

Abstract

Neutrophils and macrophages are professional phagocytic cells, extremely efficient at the process of engulfing and killing bacteria. Autophagy is a similar process, by which phagosomes recycle internal cell structures during nutrient shortages. Some pathogens are able to subvert the autophagy process, funneling nutrients for their own use and for the host's detriment. Additionally, a failure to mount an efficient autophagy is a deviation on the cell's part from normal cellular function into cell senescence and cessation of the cell cycle. In spite of these reasons, the mechanism of autophagy and senescence in leukocytes has been under studied. We advance here the concept of a common thread underlying both autophagy and senescence, which implicates PLD. Such a PLD-based autophagy mechanism would involve two positive inputs: the generation of PA to help the initiation of the autophagosome and a protein-protein interaction between PLD and PKC that leads to enhanced PA. One negative input is also involved in this process: down-regulation of PLD gene expression by mTOR. Additionally, a dual positive/negative input plays a role in PLD-mediated autophagy, β-catenin increase of autophagy through PLD up-regulation, and a subsequent feedback termination by Dvl degradation in case of excessive autophagy. An abnormal PLD-mTOR-PKC-β-catenin/Wnt network function could lead to faulty autophagy and a means for opportunistic pathogens to survive inside of the cell.