Sci. Aging Knowl. Environ., 5 April 2006
Mechanisms for protein disposal interact
Tidying up might take a bulldozer or a sponge, depending on whether the mess is a wrecked building or a spilled can of Coke. Similarly, cells rely on different mechanisms when they need to remove damaged proteins in bulk or one by one. New work suggests that, contrary to conventional wisdom, if one of these mechanisms fails, the other can take over part of its work. The results support the notion that deterioration of a particular cleanup system promotes aging.
To recover nutrients or eliminate tattered proteins, cells often consume part of their own contents through the process of autophagy (see Cuervo Perspective). In macroautophagy, a membrane-bound pouch forms in the cell and slurps up some cytoplasm. The container then carries its contents to an organelle called the lysosome for demolition. Cells can also consign specific proteins to the dustbin by using chaperone-mediated autophagy, or CMA (see "Picky Eater"). Roving molecules identify particular amino acid sequences in broken proteins and ferry them to the lysosome. After latching onto the receptor LAMP on the lysosome's membrane, the defective protein gets sucked inside and digested. Faulty CMA might foster some diseases. Cell biologist Ana Maria Cuervo of the Albert Einstein College of Medicine in New York City and colleagues have shown that abnormal proteins that accrue in an inherited version of Parkinson's disease stick tightly to the receptors but don't enter the lysosome, thereby jamming the recycling machinery (see "Stuck in the Craw"). Moreover, CMA slows as we get older and might contribute to aging by allowing toxic or worn-out proteins to accumulate and injure cells. Cuervo and colleagues wanted to gauge the cellular effects of impeding CMA in otherwise normal cells.
Lysosomes' receptors for tired proteins come in three forms, only one of which, LAMP-2A, grabs molecules and participates in CMA. To squelch production of only this variant, the researchers added RNA molecules that block the activity of the gene for LAMP-2A to mouse connective tissue cells. Protein breakdown plummeted in lysosomes isolated from these cells. Hunger usually triggers cells to fire up CMA, but the researchers expected protein recycling to fall in starving cells that lack LAMP-2A because the cells don't carry this essential piece of equipment for the process. To their surprise, the opposite happened. However, adding a compound that curtails macroautophagy prevented the surge in protein breakdown, suggesting that when CMA declined in these cells, macroautophagy ramped up. Supporting that conclusion, the team found that cells missing LAMP-2A sported more of the cytoplasm-gulping pouches essential for macroautophagy than did control cells. These results indicate that the two forms of autophagy communicate, says Cuervo. When CMA falters, macroautophagy attempts to pick up the slack. However, macroautophagy can't substitute for CMA. Compared with control cells, receptor-deficient cells are more likely to die after exposure to insults such as UV light and compounds that oxidize proteins, the scientists discovered. The work supports the suggestion that some of the deterioration of aging stems from slowing CMA, she says. The decline in protein breakdown could leave older cells more vulnerable to stress.
This work clarifies our picture of CMA's importance for cells, says cell biologist James Dice of Tufts University School of Medicine in Boston. Scientists had thought that CMA and macroautophagy didn't coordinate their activities. So the discovery that they interconnect is a big surprise, he says, and it suggests that cells can adjust the two processes to check protein buildup that might spur aging. The team also uncovered evidence that CMA interacts with the proteasome, another cellular recycler that chops up shopworn proteins, Cuervo notes. Further research could reveal how cells decide when cleanup requires a delicate touch.
April 5, 2006
Science of Aging Knowledge Environment. ISSN 1539-6150