(Press-News.org) Although the protein ITIH4 is found in large amounts in the blood, its function has so far been unknown. By combining many different techniques, researchers from Aarhus University have discovered that ITIH4 inhibits proteases in the innate immune system via an unknown mechanism. The research results have just been published in the prestigious scientific journal Science Advances.
Proteases are enzymes that cleave other proteins. Most often, proteases occur in cascade networks, where a particular event triggers a chain reaction in which several proteases cleave and thereby activate each other. Most well known is probably the coagulation cascade, which causes clotting of our blood when a vessel is punctured.
But a similar network of proteases called the complement system is found in our blood and tissues. Activation of the complement system leads to the elimination of disease-causing organisms, cancer cells, and our own dying cells. To prevent the complement system from attacking our healthy cells, it is kept under close control by proteins which inactivate the proteases after a short time; these control proteins are called protease inhibitors.
At the Department of Biomedicine at Aarhus University, Professor Steffen Thiel and PhD student Rasmus Pihl wanted to investigate which other proteins in our blood the so-called MASP proteases from the complement cascade interact with. With the help of the mass spectrometry group at the Department of Molecular Biology and Genetics at Aarhus University, led by Professor Jan J. Enghild, they found to their surprise that two MASP proteases formed a strong complex with the ITIH4 protein.
ITIH4 forms a complex with the MASP-1 and MASP-2 enzymes
"I was highly surprised when I saw the first data from our partners, showing that ITIH4 could form a complex with the MASP-1 and MASP-2 enzymes. At Biomedicine, we have been studying these two proteases for 25 years, and ITIH4 has simply never been on the radar. But it made good sense, as proteins similar to ITIH4 act as inhibitors of other proteases," says Rasmus Pihl.
Rasmus and Steffen now began a systematic study of how ITIH4 affects MASP-1 and MASP-2. It turned out that when ITIH4 formed a complex with the MASP-1 and MASP-2 enzymes, these could still cleave small proteins, while large proteins could not be cleaved when ITIH4 inhibited MASP-1 and MASP-2.
Their colleagues Jan J. Enghild and Gregers R. Andersen at the Department of Molecular Biology and Genetics nearly fell out of their chair when they learned about their discovery.
Since the 1980s, researchers at the department have characterized another protease inhibitor called A2M exactly with this property. Had their colleagues at Biomedicine now discover that ITIH4 functions similar to A2M?
To characterize in detail how ITIH4 inhibits the MASP proteases, Rasmus Pihl isolated both free ITIH4 and ITIH4 bound to the MASP-1 protease. By the use of X-ray small-angle scattering and electron microscopy, these samples were studied by postdoc Rasmus Kjeldsen Jensen and Professor Gregers Rom Andersen at Molecular Biology and Genetics. They showed that ITIH4 makes contact with the MASP-1 protease via a so-called von Willebrand domain, which matched nicely with the results from the Department of Biomedicine. This is a completely new mechanism for inhibiting proteases, and entirely different from the way A2M inhibits proteases.
"There is very little knowledge about ITIH4, but it is known that under various pathological conditions, the protein can be cleaved. Our results show that such a cleavage is absolutely necessary for the way ITIH4 can function as an enzyme inhibitor," explains Professor Steffen Thiel."
Gregers Rom Andersen explains: "By using cryo-electron microscopy, we now try to understand in detail how ITIH4 inhibits MASP-1 and MASP-2 via this new inhibition mechanism. We already know that when ITIH4 is cleaved, it forms a complex with both MASP-1 and another ITIH4 molecule. We are very excited to see how it takes place."
At one point, Winston Churchill expressed: "Men occasionally stumble over the truth, but most of them pick themselves up and hurry off as if nothing ever happened. "As a researcher, it is absolutely necessary to maintain curiosity. It is deeply fascinating to work with proteins and mechanisms that are completely new and undescribed. This also means that we do not know where we end up in terms of describing whether ITIH4 has a significance in connection with clinical situations," says Steffen Thiel.
The new results have led to a grant from the Novo Nordisk Foundation to continue the collaboration between the two departments.
Link to the research article in the scientific journal Science Advances
ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism
Rasmus Pihl, Rasmus K. Jensen, C. Poulsen, Lisbeth Jensen, Annette G. Hansen, Ida B. Thøgersen, József Dobó, Péter Gál, Gregers R. Andersen, Jan J. Enghild and Steffen Thiel
For further information, please contact
Professor Steffen Thiel
Department of Biomedicine, Aarhus University, Denmark
firstname.lastname@example.org - +45 2927 0890
Professor Gregers Rom Andersen
Department of Molecular Biology and Genetics, Aarhus University, Denmark
email@example.com - +45 30256646
There are an estimated 40,000 to 50,000 species of micro-organism per gram of soil. Addition of certain microbes can tailor soil characteristics: removing contaminants, improving fertility and even making barren land available for farming.
The Microbiology Society's report calls for increased access to research into soil health, promoting outreach activities in agricultural colleges and schools and showcasing work in non-academic outlets. This, say microbiologists, is the best way to collaborate with farmers to improve soil health and agricultural productivity.
Tilling and excessive use of fertilisers have major effects on soil health. Microbiology can be used to help understand the impact of intensive farming and design feasible mitigation practices.
The report ...
Authors from the German Center for Diabetes Research (DZD) presented data showing that the longevity gene mammalian Indy (mINDY) is involved in blood pressure regulation in the Journal of Clinical Investigation (JCI) insight. Reduced expression of mINDY, which is known to extend life span in lower organisms and to prevent from diet induced obesity, fatty liver and insulin resistance in mice, has now been shown to lower blood pressure and heart rate in rodents. The authors provided mechanistic insights for the underlying physiological mechanism based on in vivo data in a genetic knock out model as well as microarray and in vitro studies. Furthermore, ...
Children determine emotion by what they hear, rather than what they see, according to new research.
The first-of-its-kind study, by Durham University's Department of Psychology, looked at how children pick up on the emotions of a situation.
They found that whilst adults prioritised what they see, young children showed an auditory dominance and overwhelmingly prioritised what they could hear.
The researchers say their findings could benefit parents currently managing home learning and professional educators by increasing their understanding of how young children pick up on what is going on around them.
The research may also provide new avenues to understanding ...
Theories were introduced as far back as the 1960s about the possible existence of superheavy elements. Their most long-lived atomic nuclei could give rise to a so-called "island of stability" far beyond the element uranium. However, a new study, led by nuclear physicists at Lund University, shows that a 50-year-old nuclear physics manifesto must now be revised.
The heaviest element found in nature is uranium, with a nucleus containing 92 protons and 146 neutrons. The nuclei of heavier elements become more and more unstable due to the increased number of positively charged protons. They therefore decay faster and faster, usu-ally within a fraction of a second. ...
As the world prepares to commemorate International Holocaust Remembrance Day on January 27th, communities and memorials around the world are addressing how to meaningfully commemorate the day while protecting public health and safety. The day marking the anniversary of the liberation of Auschwitz is ordinarily commemorated with hundreds of individual memorial events across the globe. This year, most of those events will be impossible for any sizable gathering of people due to COVID-19.
With the goal of proposing relevant solutions to this challenge, Dr. Tobias Ebbrecht-Hartmann and research student Tom Divon of the Hebrew ...
ATLANTA - JANUARY 26, 2021 - A new study shows 4 in 10 cancer deaths are attributable to cigarette smoking in parts of the South region and Appalachia. For this study, appearing in Cancer Causes & Control, Farhad Islami, MD, PhD, and colleagues at the American Cancer Society examined the proportion of cancer deaths from 2013 to 2017 attributed to cigarette smoking in 152 metropolitan and micropolitan statistical areas (MMSAs).
Data show the proportion of cancer deaths attributable to cigarette smoking was greater in men than in women in all evaluated MMSAs. In both sexes combined, the proportion of smoking-related cancer deaths ranged from 8.8% in Logan ...
The battle to stop false news and online misinformation is not going to end any time soon, but a new finding from MIT scholars may help ease the problem.
In an experiment, the researchers discovered that fact-checking labels, when attached to online news headlines, actually work better after people read false headlines, compared to when they precede the headline or accompany it.
"We found that whether a false claim was corrected before people read it, while they read it, or after they read it influenced the effectiveness of the correction," says David Rand, an MIT professor and co-author of a new paper detailing the study's results.
Specifically, the researchers found, when "true" and "false" labels were shown immediately after participants in the experiment read headlines, ...
A new neural network developed by researchers at the University of Eastern Finland and Kuopio University Hospital enables an easy and accurate assessment of sleep apnoea severity in patients with cerebrovascular disease. The assessment is automated and based on a simple nocturnal pulse oximetry, making it possible to easily screen for sleep apnoea in stroke units.
Up to 90% of patients experiencing a stroke have sleep apnoea, according to earlier studies conducted at Kuopio University Hospital. If left untreated, sleep apnoea can reduce the quality of life and rehabilitation of patients with stroke and increase ...
An estimated 48 million cases of foodborne illness are contracted in the United States every year, causing about 128,000 hospitalizations and 3,000 deaths, according to the Centers for Disease Control (CDC). In some instances, the source is well known, such as a batch of tainted ground beef that infected 209 people with E. Coli in 2019. But 80 percent of food poisoning cases are of unknown origin, making it impossible to inform consumers of hazardous food items.
David Goldberg, assistant professor of management information systems at San Diego State University, wants to improve the traceability and ...
Phycocyanobilin (PCB) is a natural blue chromophore found in cyanobacteria. PCB is expected to be applied as food colorants and pharmaceuticals with anti-inflammatory and antioxidant properties. PCB also functions as the chromophore of photoswitches that control biological functions in synthetic biology. PCB is covalently bound to phycocyanin, a component of photosynthetic antenna protein, and its extraction requires specialized expertise, time-consuming procedures, and/or expensive reagents. A research group led by Assistant Professor Yuu Hirose at Toyohashi University of Technology succeeded in developing a highly efficient and rapid extraction method for PCB by treating cyanobacterial cells with alcohol ...