Scientists Identify Protein Critical for Iron Absorption

By Eric Sauter

Scientists at The Scripps Research Institute have pinpointed an important protein that is essential for the normal absorption of iron in the body. The discovery could lead to novel therapies to block anemia during chronic diseases or to treat hemochromatosis, a genetic disease caused by an overabundance of iron.

The study was published May 1, 2008, in Science Express, an advance, online edition of the journal Science.

"Iron is fundamentally important to all forms of life, but before our study no one knew precisely how higher organisms detect iron deficiency and upregulate iron absorption to correct it," said Bruce Beutler, chair of the Scripps Research Department of Genetics who led the research. "The findings reveal the first molecular component of a pathway that detects iron deficiency, and helps produce a homeostatic response."

In the new study, the researchers describe their discovery that a protein called TMPRSS6, a cell surface protease, suppresses gene expression of the hormone hepcidin, a liver peptide that acts as the master regulator of intestinal iron absorption and release of iron from the tissues. Under normal circumstances, body iron content is tightly regulated, and pathways for the increase or suppression of hepcidin are activated in response to iron excess or iron deficiency.

The researchers found that a splicing error in the TMPRSS6 gene disrupted normal iron regulation, causing anemia.

The scientists discovered the key role of TMPRSS6 in maintaining iron balance through a mutant mouse that they created using a chemical mutagen. They named the mutant strain Mask, because the mouse loses its body hair while retaining facial hair. The Mask mice proved to be iron deficient and anemic because they lacked the ability to absorb iron normally. In the normal mouse, both iron deficiency and anemia decrease the expression of hepcidin, leading to increased iron absorption—but not in these mice.

"We discovered that the Mask mouse was insensitive to low iron levels and failed to suppress hepcidin production," Beutler said. "If iron is depleted, the body needs a mechanism to sense the deficiency and to increase iron absorption from the diet. TMPRSS6 turned out to be an essential component of this low-iron detection pathway, one that is independent of previously understood hepcidin gene activation pathways." 

Good Iron, Bad Iron

The study showed that TMPRSS6 suppresses a number of positive stimuli that lead to increased hepcidin expression and that it does so in part by a proteolytic mechanism. Proteases, sometimes referred to as garbage cans with teeth, can digest other molecules and are required for a number of activities including blood clotting and programmed cell death.

The authors concluded that under conditions of iron deficiency, TMPRSS6 most likely cleaves itself, and then signals from the cell surface, leading to a shutoff of the hepcidin gene. The nature of the signals elicited by TMPRSS6 remain unknown, but are rather specific, and do not affect a large number of other genes.

Iron is a critical cofactor for a number of important metabolic reactions, including the function of the oxygen carrier hemoglobin, making anemia a potentially serious health problem. The prevalence of iron deficiency anemia is 2 percent in adult men, 9 to 12 percent in non-Hispanic white women, and nearly 20 percent in black and Mexican-American women, according to the American Academy of Family Physicians.

Even though iron is necessary to sustain life and iron deficiency is one of the most common maladies of humans, iron can also be toxic when present in excess. Hemochromatosis is the result of increased body iron, and can cause severe organ damage.

"From a clinical perspective," Beutler said, "one can imagine manipulating TMPRSS6 in either direction in terms of therapeutic possibilities. If you block this pathway, you decrease iron in the body. If you stimulate the pathway body iron increases. Now that we have discovered a part of the pathway that detects iron deficiency, we can begin to think of ways to use this new knowledge therapeutically. Because TMPRSS6 is a protease, there are well known methods to find selective antagonists for it." 

Because mice with the Tmprrs6 mutation are iron deficient, the scientists reasoned that naturally occurring mutations of the human counterpart of the gene might also produce iron deficiency that was resistant to iron treatment. The Beutler group and others have now found a number of such patients, defining a new genetic disease of humans.

Other authors of the study include Xin Du, Terri Gelbart, Ellen She, Eva Marie Y. Moresco, Jaroslav Truksa, Pauline Lee, Yu Xia, Kevin Khovananth, Suzanne Mudd, Navjiwan Mann, and Ernest Beutler of The Scripps Research Institute.See
http://www.sciencemag.org/cgi/content/abstract/1157121

The study, The Serine Protease TMPRSS6 Is Required to Sense Iron Deficiency, was supported by the National Institutes of Health, the Skaggs Institute for Chemical Biology, and the Stein Endowment Fund.

Send comments to: mikaono[at]scripps.edu

"Iron is fundamentally important to all forms of life, but before our study no one knew precisely how higher organisms detect iron deficiency and upregulate iron absorption to correct it."

—Bruce Beutler