When a protein isn’t folded correctly, it can’t function properly. This has the potential to wreak havoc on a cell – and a person. The underlying cause of cystic fibrosis provides a good example of how even a small mistake in protein folding can lead to a big health problem. In this disease, a person inherits a mutated gene encoding a protein called CFTR. Because of this mutation, CFTR is not folded into its proper shape. The cell degrades the misfolded protein, leading to poor lung function, digestive problems and other complications.Most protein folding problems occur when the endoplasmic reticulum (ER) is stressed. The ER is a cellular organelle that specializes in folding proteins that are destined to be anchored in the cell surface or secreted. When the ER’s load of unfolded or misfolded proteins outweighs its ability to fix them, ER stress can result. The cell is usually able to correct this problem by triggering the unfolded protein response. This process slows protein production, enhances protein folding, and clears away any that have been misfolded. ER stress also slows the process of cell division.
“Although it has been observed that ER stress halts cell reproduction, it is not well understood how and why this happens,” explains Dr. Mei-Fan Chen, who recently received her Ph.D. from UC San Diego for research she conducted in Dr. Ze’ev Ronai’s lab.
A protein called Ufd1 is the main character in Dr. Chen’s story. Ufd1 is an adaptor protein, meaning that it acts as a middle man, bringing together other proteins to perform a cellular function. Under the mentorship of Dr. Ronai and postdoctoral researcher Dr. Gustavo Gutierrez, Dr. Chen began her project just trying to determine whether Ufd1 regulates the mammalian cell cycle – the cell’s process of duplicating its DNA and dividing into two identical “daughter” cells. To find out, she inhibited expression of Ufd1 and looked at the effect on a panel of proteins related to the cell cycle. One in particular stood out – a protein called Skp2, which regulates the cell’s entry into the phase of the cell cycle where cells duplicate their DNA. When Ufd1 is reduced, so is Skp2. She eventually found that ER stress dampens Ufd1 function and therefore inhibits Skp2, leading to a delay in the cell cycle. Delving deeper into the mechanism, she also identified other proteins that contribute to Ufd1’s effect on Skp2.
“We knew that ER stress puts the cell cycle on hold. In this study, we identified new players involved in that process,” Dr. Chen says. “We also provide initial evidence that one phase of the cell cycle – called G1 – allows efficient clearance of misfolded proteins, giving functional significance to ER stress-dependent cell cycle delay.”
These results, published May 9 in the journal Proceedings of the National Academy of Sciences USA (PNAS), show how Ufd1 helps orchestrate a previously unknown link between ER stress and the cell cycle. And since ER stress has been implicated in many human diseases, a new appreciation of the cell cycle’s role in this process could improve our understanding of conditions ranging from Alzheimer’s disease to cancer.
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Original paper:
Chen M, Gutierrez GJ, & Ronai ZA (2011). Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control. Proceedings of the National Academy of Sciences of the United States of America, 108 (22), 9119-24 PMID: 21571647
