Part of a cellular mechanism that regulates the folding of new proteins into their proper shapes also includes a genetic response that enlarges the factory where both protein folding and packaging of proteins occurs. This finding, from researchers at St. Jude Children’s Research Hospital, Loyola University (Chicago) and Kyoto University (Kyoto, Japan), are published in the Oct. 15 issue of the Journal of Cell Biology.
The link between protein folding and factory construction ensures that the two processes are coordinated when the cell is called upon to quickly make, fold and secrete large amounts of specific proteins.
The investigators discovered that the cell makes a molecule called XBP1 in response to an increased demand on the protein-folding machinery. This increased demand for folded proteins triggers the so-called unfolded protein response (UPR), as well as the expansion of the factory where proteins are folded and packaged so they can be secreted from the cell. The UPR also prompts the cell to make molecules called chaperones, which do the actual task of protein folding.
XBP1 triggers the cell to make phosphatidylcholine, the major building block of the rows of membranes that make up much of the factory, which is called the endoplasmic reticulum (ER). Membranes in the ER serve as envelopes to package the folded proteins.
After leaving the ER, the envelope fuses with the inside face of the membrane that surrounds the cell itself. Once fused to the cell’s membrane, the envelope pops open, ejecting the protein out of the cell.
“By linking chaperone production to the synthesis of phosphatidylcholine, XBP1 coordinates the processes of building and equipping new ER to increase the cell’s capacity for folding and shipping proteins,” said Suzanne Jackowski, Ph.D., a member of St. Jude Infectious Diseases. Jackowski is an author of the Journal of Cell Biology report.
The study explains how the cells are able to rapidly meet the need for increased production of specific proteins by coordinating the tasks of folding and packaging them.
The need for close coordination of protein processing and packaging is especially critical in the case of antibody production, according to Joseph W. Brewer, assistant professor in the department of Microbiology and Immunology at Loyola University Medical Center. The cells that make and secrete antibodies—the B cells—must synthesize, fold and release thousands of these proteins per minute, in response to an infection. Brewer is senior author of the paper.
The researchers made their findings in mouse cells called fibroblasts. They inserted the gene for XBP1 into a virus and used the genetically modified virus to transfer the gene into the fibroblasts. The XBP1 gene triggered an increase in the activity of key enzymes involved in membrane production. Because it is already known that UPR triggers activation of the XBP1 gene, findings of the current study suggest that XBP1 links the expansion of ER to the increased ability to fold and package newly made proteins for secretion.
Other authors of this paper are Rungtawan Sriburi (Loyola University) and Kazutoshi Mori (Kyoto University).
This work was supported in part by the National Institutes of Health, a Cancer Center (CORE) support grant and ALSAC.
<b>St. Jude Children's Research Hospital</b>
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.
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