How Cells Return to Normal After Responding to Stress

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New research from the University of North Carolina at Chapel Hill School of Medicine describes how cells recover from heat, cold and other stressful conditions.

The findings also could have implications for the development of new therapies for cardiovascular diseases and neurodegenerative diseases such as Alzheimer’s.

The study, which appears in the March 23 issue of Nature, was led by Dr. Cam Patterson, Ernest and Hazel Craige distinguished professor of cardiovascular medicine, chief of the Division of Cardiology and director of the Carolina Cardiovascular Biology Center. Patterson also is a member of the UNC Lineberger Comprehensive Cancer Center.

The research explores the role played by the protein CHIP in the cell’s response to stress. The Patterson laboratory cloned the protein in 1999.

In the setting of stress, molecules known as heat shock proteins are synthesized by the cell to provide protection against protein damage. These heat shock proteins, Hsp’s, are an important part of a large protein family known as molecular chaperones. Molecular chaperones help new or distorted proteins fold into the correct shape, which is essential to their function.

“Molecular chaperones determine whether proteins are appropriately folded,” Patterson said. “They help proteins to fold normally when proteins are being made, and they help the cell to find damaged proteins under stressful circumstances. Once those damaged proteins are found, the cell either tries to refold them or to get rid of them somehow.”

CHIP is a co-chaperone, meaning that it associates with the molecular chaperone Hsp70 and regulates its activity. But CHIP also has another function - as an ubiquitin ligase.

“Ubiquitin ligases are generally involved in tagging proteins with a signal that allows them to be recognized by the proteasome, which is the major garbage can for proteins in a cell,” Patterson said. “Our model is that CHIP is the protein that is responsible for targeting chaperone substrates for degradation. The thinking is that when a protein is too damaged to be refolded, CHIP ubiquitinates that protein so that it can be degraded.”

The results present a previously unknown mechanism for how the cell determines whether or not to degrade misfolded proteins or to degrade the heat shock proteins that have been produced so that it can then resume its physiologic activities.

“We think that the stress response is required to protect cells from damage during stress, but it is also important to let the cells return to the normal condition as soon as possible,” said Dr. Shu-Bing Qian, postdoctoral researcher in the Patterson lab and first author of the study.

They found that during stress heat shock proteins attempt to refold proteins. And if unsuccessful, CHIP tags those proteins for degradation. Once all the proteins that have been tagged for degradation have been removed by the proteasome, a barrel-shaped complex of proteins that digests other proteins, CHIP begins to tag the heat shock proteins themselves for degradation. Once they are all removed, the cell can go back to business as usual.

Patterson’s group has made mouse models lacking CHIP and has found that the mice are more susceptible to many different stressful circumstances, such as fever and heart attacks.

“That finding seems to be due to the accumulation of misfolded proteins,” said Patterson. “Chronic dysregulation of the CHIP molecular pathway would also be expected to be maladaptive.”

One hope is that this finding could be extended to human diseases where a faulty stress response has already been implicated.

Patterson said there are specific diseases in which chronic protein misfolding is critical, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. “So we expect that CHIP would play an important role in cellular adaptation under those circumstances as well.”

He said the design of drugs to enhance the activity of CHIP might be a valid approach to treating diseases of protein misfolding or chronic stress.
Along with Patterson and Qian, co-authors on the study include technician Holly McDonough and postdoctoral researcher Dr. Frank Boellman, both of the Carolina Cardiovascular Biology Center, and collaborator Dr. Douglas M. Cyr, associate professor of cell and developmental biology.

Funding for the research came from the National Institute of General Medical Sciences, National Institute on Aging, the American Heart Association, and the Burroughs Wellcome Fund.

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