Sci. Aging Knowl. Environ., 15 September 2004
Vol. 2004, Issue 37, p. nf84
[DOI: 10.1126/sageke.2004.37.nf84]


Fatal Distraction

Disciplining misshapen proteins leaves cells vulnerable to oxidative stress and death

Mary Beckman

If an entire police force rushes to quell a political protest, muggers can prey on citizens unchallenged. Similarly, new research shows that the system called in to fix badly shaped proteins can exhaust resources needed to protect the cell from reactive oxygen species (ROS), leaving the cell prone to damage and death.

Many diseases, from diabetes to Alzheimer's, result from misshapen proteins that gum up the cell's proteinmaking machinery. A malformed protein can resemble a jacket whose snaps don't align correctly if sulfur molecules in the protein pair up in the wrong pattern. In response, a quality-control squad known as the unfolded protein response (UPR) prompts protein reshapers to undo the snaps and refasten them in the correct configuration. If fixing them is impossible, UPR stimulates trash collectors to clear out unusable proteins. Researchers have noticed that when disheveled proteins overwhelm the UPR, cells die; Haynes and colleagues wondered why.

To find out, they exploited yeast that overproduce a protein known as CPY*, which carries a mutation that prevents it from being snapped together correctly (see "Groovy Protein QC, Man"). When the team disabled the yeast's protein-disposal system, the cells died off as CPY* accrued in the endoplasmic reticulum (ER), the cell's protein manufacturing plant. But if the team disrupted the UPR alarm as well as protein disposal, abundant CPY* did not kill cells, indicating that the UPR exacts that toll. Next, the team found that quantities of toxic ROS rose in the ER when CPY* built up. Supplementing the culture with extra glutathione, a molecule that mops up ROS within cells, saved the yeast. Together, the results suggest that in the face of a deluge of unfolded proteins, the UPR somehow unleashes a flood of ROS, which kills cells.

The researchers next examined whether protein groomers release ROS as they snap and unsnap protein bonds, as previous work had hinted. When the researchers genetically modified the CPY*-producing yeast to make gobs of a key protein reshaper, the cells made even more ROS. Also, if the researchers removed the sulfur "snaps" in CPY*, cells did not die, suggesting that the unfolded proteins don't kill cells, but that ROS resulting from the protein-fixing process does. Together, these results hint that as cells repeatedly attempt to repair the unfixable CPY*, ROS accumulate in the ER and deplete the cell's natural supply of glutathione, leaving the cell unable to extinguish the oxidative fire.

The work "convincingly establishes that the ER is a source of oxidative damage," says protein biochemist Jonathan Weissman of the University of California, San Francisco. Oxidative stress resulting from the cell's attempts to deal with misshapen proteins "can possibly contribute to diseases and aging. This is an important avenue to explore," he says. Biochemist Wulf Paschen of the Max Planck Institute for Neurological Research in Köln, Germany, agrees but points out that the newfound idea that ill-formed proteins in the ER can exacerbate oxidative damage is "a long way to any treatment" for diseases caused by accumulation of bad proteins. Further studies might show researchers how to help aging cells incarcerate molecules that rob them of life.

September 15, 2004
  1. C. M. Haynes, E. A. Titus, A. A. Cooper, Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol. Cell 15, 767-776 (2004). [CrossRef][Medline]
Citation: M. Beckman, Fatal Distraction. Sci. Aging Knowl. Environ. 2004 (37), nf84 (2004).

Science of Aging Knowledge Environment. ISSN 1539-6150