Several processes are essential for a cell to survive for long enough to proliferate. The release energy from chemical stores and the production of the machinery and structural components that make up the cell are well-understood, as is the disposal of waste. Smaller rubbish is generally easily dealt with, much of it diffuses out of the cell, requiring no further effort. But what about, for example, the material that is left after an infection?
Such debris constitutes large waste and is not material that can be expected to leave the cell by passive flow through the plasma membrane. This waste requires so-called Active Transport, a system that requires a co-ordinated effort to expel material through one or more membranes, including the plasma membrane. The steps are relatively straight forward, the material is rounded up and a membrane is wrapped around it forming a vesicle. The vesicle is taken to the plasma membrane, and the two membranes merge, expelling the contents of the vesicle into the extracellular medium.
So far, so intuitive. But how is this process, called exocytosis, controlled? What stops healthy or even essential material being lost this way, and how is all the cytotoxic* material expelled? These and other questions have been researched by cell biologists working on exocytosis. The control mechanism has received recent attention, with results showing that not only do lipids form the capsule that the waste is expelled by, but that lipids within that bilayer form part of the control mechanism. Recent work has focussed on how these control mechanisms operate, so that in disease states in which exocytosis is important, it may be manipulated accordingly. This has led to our being treated to two studies on the same subject, in the same journal, published at the same time.
The two papers offer a tantalising picture of what may occur through the whole control mechanism. Yamaga et al. report that removing a protein called PLC, that metabolises a signalling lipid, increases exocytosis . In other words, the substrate for PLC increases exocytosis. The substrate is an old friend of this blog, PIP2.
Rogasevskaia & Coorssen  investigate another protein that is also known to act on PIP2. This protein is called PLD and is related to PLCs, but produces a different product, which is itself a signalling molecule. This molecule is called PA and is distinct from the lipid-like signalling molecule produced by PLC activity, called DAG.
The effects of PLD in producing PA are a modulation of the docking that occurs between the wrapped up waste (vesicle) and the plasma membrane (through which it must pass to be outside the cell) . The effect of reducing PIP2 through PLC activity promoted dismantling of part of the cytoskeleton . This makes it easier for incoming vesicles to meet with the plasma membrane and complete exocytosis.
These two observations invite several questions and observations. First, how do the PLC and PLD involved compete for the substrate? Having PIP2 around seems to help exocytosis to occur, but so does one of its products, DAG—or at least an absence of PIP2. Is PIP2 sacrificed for the good of the process, handing over the baton of waste management to younger lipids as it does so? It seems possible. What may also be required is a co-ordination of the amounts and activity of the PLD and PLC. It may also be necessary to control where they are, so that they PIP2 is sacrificed in the right way at the right moment.
What this work makes clear is that inositides and PIP2 in particular have a crucial role in cellular egestion as well as other signalling, such as proliferation and glucose metabolism. This underscores the question of how one lipid can have so many functions simultaneously and the control of all of them be retained.
References and Notes
*The prefix ‘cyto’ refers to cells. Thus, cytotoxic means toxic to cells, which may not be the same as toxic to organisms. Cytoskeleton is an internal structural support that contributes to the cell’s shape. Background on exocytosis and its antonym, endocytosis can be found here.
 M. Yamaga, D. M. Kielar-Grevstad, T. F. J. Martin, J. Biol. Chem., 2015, 290, 29010–29021. DOI 10.1074/jbc.M115.658328
 T. P. Rogasevskaia, J. R. Coorssen, J. Biol. Chem., 2015, 290, 28683–28696, Doi 10.1074/jbc.M115.681429
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