Inflammatory disease study yields knockout results

Research provides insight into how a protein might help protect against bowel disease.

The occurrence rates of digestive tract disorders known collectively as inflammatory bowel diseases (IBDs) appear to have been rising in Western countries for about 70 years, and the reasons remain unclear. IBDs, of which the most common forms are Crohn’s disease and ulcerative colitis, are autoimmune disorders that cause the body’s immune system to attack the colon and small intestine of the digestive tract.

Nara Institute of Science and Technology (NAIST) researchers have been using gene knockout mice to explore the function and physiological significance to IBD of a poorly understood stress sensor known as inositol-requiring enzyme 1β (IRE1β), which is expressed selectively in the mammalian digestive tract. This is involved in activating a process called the unfolded protein response (UPR), although researchers don’t know how.

“There are several stress sensors in the UPR pathway, but among these IRE1β is one of the least understood,” explains Akio Tsuru, from NAIST’s Molecular and Cell Genetics Laboratory. “Previous studies suggested that IRE1β plays a role in preventing intestinal bowel disease, but the mechanism behind this function is completely unknown.”

The correct topology — shape, geometry and orientation — of proteins is vital for cells to function correctly. Newly synthesized proteins pass into the endoplasmic reticulum (ER), a specialized cellular subunit that folds and modifies them to their required topology. If, however, the influx of proteins to the ER exceeds its capacity, unfolded or misfolded proteins accumulate and ER stress results. Activating the UPR is an important way that cells respond and if the UPR is unable to deal with the stressed conditions, then apoptotic (programmed) cell death is initiated.

“The UPR is now a popular area of research because of the links between ER stress and many other diseases as well, such as Parkinson’s,” says Tsuru. “Our study has revealed that IRE1β located in the ER of goblet cells in the digestive tract regulate and optimize mucin [the main component of mucus] production. It enables the efficient secretion of mucin, which protects the digestive tract surface from intestinal bowel disease.

“Finding the location of cells expressing IRE1β and identifying the relationship between IRE1β and mucin production are breakthroughs in our understanding of IRE1β function."

This article was first published in the NAIST Research Highlights 2016 Booklet. Read the original article here