Groovy Protein QC, Man
Authors: Beckman Mary 
Published: August 2003

Responsible automobile manufacturers check the quality of parts before a vehicle leaves the factory. Similarly, cells monitor new proteins for defects before flaws can disable finely tuned processes. But if too many faulty sprockets come down the assembly line, they can overwhelm inspectors and sneak through the checkpoint. Now, scientists have uncovered a backup system--known as HIP--that disposes of proteins that escape quality control (QC). The system might represent a secondary line of defense against protein defects that lead to age-related degenerative diseases.

After their amino acids have been linked into a chain, proteins bound for destinations outside the cell fold into their final shape within a compartment called the endoplasmic reticulum (ER). Several watchdog molecules that make up the so-called HRD/DER pathway check for deviants and tag rumpled proteins for disposal in the cellular crematorium, known as the proteasome. Because many diseases, such as Alzheimer's and Parkinson's, seem to result from disfigured proteins, researchers are striving to understand how cellular surveillance mechanisms go awry.

While studying
Saccharomyces cerevisiae
with defects in the HRD/DER pathway, Haynes and colleagues discovered that the fungi retain the ability to trash a misshapen test protein--called CPY*--albeit more slowly than normal yeast do. The researchers wondered how this new cleanup mechanism--which they termed HIP--operates. To find out, the group further tinkered with the yeast cells so that they also churned out large amounts of CPY*. When the yeast produced eight times more CPY* than normal, they butchered the mutant protein as fast as when the main QC system was intact. In addition, the protein breakdown occurred outside, rather than inside, the ER. The researchers concluded that when abnormal proteins abound, HIP kicks in and clears faulty molecules that swamp the HRD/DER system and escape the ER.

To determine whether HIP and HRD/DER send trash to the same landfill, the team tracked CPY* in yeast that harbored defective proteasomes and a crippled HRD/DER pathway. Those cells got rid of CPY* more slowly than did cells with intact proteasomes, indicating that HIP relies on the garbage dumps to decompose abundant CPY*. Additional biochemical analysis revealed that proteins disposed of by HIP carry ubiquitin tags, molecular tickets to the proteasome. The team sifted through 36 possible tagging enzymes and found one--called Rsp5--that participates in HIP but is not part of the HRD/DER team. Together, the data suggest that yeast carry a protein-disposal system distinct from HRD/DER that handles large numbers of misfolded proteins if they blow past ER security.

Cell biologist Ronald R. Kopito of Stanford University in California says the results are surprising in light of "the dogma that misfolded proteins don't leave the ER." However, mutations that cause proteins to accumulate abnormally--as occurs in Parkinson's disease--might overwhelm a cell's QC system, he says. Understanding how cells deal with defective proteins could help scientists flesh out why those molecules sometimes persist and lead to diseases of aging. Such knowledge could suggest ways to beef up QC in our sunset years.

--Mary Beckman

C. M. Haynes, S. Caldwell, A. A. Cooper, An
HRD/DER
-independent ER quality control mechanism involves Rsp5p-dependent ubiquitination and ER-Golgi transport.
J. Cell Biol.
158
, 91-102 (2002).
[Abstract]
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