Cellular 'garbage disposal' system

Cellular 'garbage disposal' system
Credit: Alzforum

In a recent research study in the US, a subset of protein complexes whose role has long been thought to consist only of chemically degrading and discarding of proteins no longer needed by cells appears to also play a role in sending messages from one nerve cell to another.

The investigators say the work could eventually open new paths in research about learning, memory and brain disease.  Since the discovery of the proteasomes in 1980,  they have long been considered part of cells’ “ garbage disposal” system, explains a doctoral student. "Once unwanted proteins are delivered to proteasomes, these large complexes act like a paper shredder. They cut proteins into tiny pieces, these pieces are then reused to make new proteins”, he explains. And its basically a way of recycling proteins in cells”.

Because this process takes hours or days to complete, blocking proteasomes' activity with chemical inhibitors shouldn't affect any shorter-term cellular functions. However, previous research has shown that these chemical inhibitors can rapidly affect signaling across neurons within seconds.

Wondering whether some traditional assumptions about proteasomes might be wrong, the researchers first looked to see if proteasomes might be located beyond the cytoplasm. Using immuno- electron microscopy, proteasomes were searched for in cultured mouse neurons, using proteins labelled by antibodies in cells.

The researchers found that some proteasomes were embedded in the cells’ membranes, a place where these protein complexes had not been seen before. Further, using membran fractionation- a biochemical test, the researchers separated the membrane  from other parts of the cell and looked to see what components are present.

The researchers then turned their attention to figuring out what these proteasomes were doing in this unusual location. Knowing that proteasomes usually degrade proteins, the researchers applied radioactive amino acids -- components that make up proteins -- to neurons to label proteins made inside neurons.

Biochemical approaches showed that these amino acids were incorporated into all proteins. Soon after, peptides (small units of proteins) that carried these radioactive amino acids were pumped to the outside of cells. When the researchers treated neurons with a chemical inhibitor that only blocked the membrane proteasome, they saw that this inhibitor blocked this release of peptides outside the cell. This suggested that the membrane-bound proteasome had degraded the tagged proteins and expelled them to the cell exterior.

When the researchers treated groups of neurons with their chemical inhibitor of the neuronal membrane-bound proteasomes, they found that calcium signaling between these cells went awry. Because calcium signaling is essential to cell-to-cell communications, these results suggested that the expelled peptides might be important for cellular messaging.

These findings suggest that the neuronal membrane-bound proteasome is vitally important for cell signaling. Their experiments bring up a host of new questions about what specific proteins this complex is degrading, what compounds it's expelling and what happens when this system breaks down, says the researchers.