|MadSci Network: Cell Biology|
Dear Julya, You can imagine that the lysosome’s destructive environment would make quick work of anything, including itself and the cell that contains it. It is remarkable that the lysosome remains intact and, though I’m not aware of a complete explanation for this, I can tell you about a couple ideas that are floating around in scientists’ minds. First, let’s review what you probably know already. A lysosome is an organelle that is responsible for breaking down big molecules. These molecules can come from outside or inside the cell, and can be parts of microbes that the cell must kill to protect itself. If you look at all the lysosomes in a cell, you find that their shapes can be quite diverse. This may be reflective of several kinds of lysosomes, each suited for a particular role: extracting nutrients from things the cell has absorbed, killing microorganisms, or breaking down debris. These various organelles are defined as lysosomes because they all have a high concentration of enzymes known as acid hydrolases—“hydrolases” because they hydrolyze, or break apart, other things and “acid” because they require a low-pH environment for optimal function. These acid hydrolases include nucleases, which target nucleic acids like those in DNA and RNA; proteases, which target proteins, glycosidases, which target sugars; and lipases, which target lipids. Remember that enzymes are characterized by “substrate specificity,” which means that they can only act on molecules of a certain shape (a shape that fits that enzyme’s active zone). This is our first clue to how lysosomes can protect themselves from their own enzymes—if the enzymes can’t fit lysosome parts into their active zones, then those lysosome parts are safe. In fact, it is known that proteins in the lysosome membrane have an uncommonly large number of sugar molecules stuck to them. These sugars act as a shield, keeping many acid hydrolases from segments of protein that they would otherwise recognize and chop up. The process of adding sugars to other things is called “glycosylation,” and a protein with sugars on it is said to be a “glycoprotein.” Of course, the lysosome contains glycosidases as well, and so those protein shields probably don’t last forever. This imperfect protection of a lysosome’s parts may actually be good for the cell. If the lysosome has evolved ways to protect itself from its enzymes, then it is likely that microbes can evolve those same mechanisms. It is to the lysosome’s advantage to have enough safeguards to keep itself intact for a reasonable amount of time, but not so many that pathogens can hijack those safeguards to their own cell-killing purposes. Furthermore, anything the cell makes lysosome-proof will probably end up accumulating in lysosomes, where it takes up precious space and cannot be recycled for other cellular processes. Thus, if it means that lysosomes get the ability to destroy many things, it is okay if they damage themselves in the process. What matters is how fast they do so; if it isn’t too fast, then the cell can replace or repair the damage and keep the lysosome intact. You then get the best of both worlds: a lysosome that can chew up a wide variety of things but that also stays in one piece. What happens if the lysosome ruptures? It appears as if the lysosomal contents would wreak havoc. In actuality, the cell is protected by the neutral pH of its cytoplasm. Without an acidic environment, the acid hydrolases are inhibited such that their threat to the cell is minimized. The pH of cytoplasm is 7.2, while that of lysosomes is around 5. Because pH is on a logarithmic scale, there are more than two orders of magnitude between the ideal environment for acid hydrolases and the intracellular environment—this is a reasonable margin of safety. In summary, lysosomes must maintain a balance between destroying themselves and being ineffective at digesting many molecules. They probably protect themselves just enough to buy time for maintenance by other cellular processes. It would be very interesting to identify the various proteins, lipids, and sugars in the lysosome membrane, identify the targets of the acid hydrolases, and then see how much those two groups overlap. One could then get an idea of how much of the lysosome is prone to self-digestion. It would also be interesting to know what various bacteria have evolved to protect themselves from lysosomes, and then see if these bacterial defenses are copies of devices lysosomes use to extend their own lifespan. Most of this information was taken from Molecular Biology of the Cell, an excellent textbook written by Bruce Alberts and colleagues. Best, Michael
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