Featured Research

from universities, journals, and other organizations

Paradigm Shift In Immune Response Regulation

Date:
March 26, 2009
Source:
Goethe University Frankfurt
Summary:
Over the past decade various pieces of the puzzle how signal transmission controls immunity have been coming together. Now, scientists report a paradigm shift in the regulation of immune response. Their results show that interaction with a linear ubiquitin chain is crucial for nuclear factor kappa B activation. Their findings may also contribute towards structure-based drug design to target the defective NF-kappa-B pathway in diseases such as cancer, inflammation and immunodeficiency.

Over the past decade various pieces of the puzzle how signal transmission controls immunity have been coming together. Now, in Cell an international team reports a paradigm shift in the regulation of immune response. Their results show that interaction with a linear ubiquitin chain is crucial for nuclear factor kappa B activation.

Related Articles


Their findings may also contribute towards structure-based drug design to target the defective NF-κB pathway in diseases such as cancer, inflammation and immunodeficiency.

The body's first line of defence against bacteria and viruses is the innate immune system where phagocytes identify the foreign organism and initiate an alarm reaction, often accompanied by inflammation. As a consequence, molecular cues are produced in the blood, such as Tumor Receptor Factors (TNF) or interleukin-1, and these stimulate further reactions in the immune system. But what exactly happens after the molecular cues have docked onto the cell receptors that specialize in immune response? What is the basis of signal transmission from the cellular receptors into the cellular interior?

Over the past decade, the overall picture of this large puzzle has been gradually pieced together to show that modifications in the cell protein - including the addition of phosphate groups (phosphorylation) or the conjugation of small modifier ubiquitin (ubiquitination) - play a central role in controlling the immune system.

Scientists at Frankfurt's Goethe University led by Prof. Ivan Dikic have established an international collaboration to investigate the role of ubiquitin modification in these pathways. The international team includes the laboratories of Soichi Wakatsuki (Photon factory, Tsukuba, Japan), Fumiyo Ikeda (MedILS, Split, Croatia), Felix Randow (LMB, Cambridge, UK) and David Komander (LMB, Cambridge, UK). They have been investigating how a transcription factor known as the nuclear factor kappa-B (NF-κB) coordinates the gene expression necessary for the cell's immune response. NF-κB is activated by an enzyme (IkappaB-Kinase, IKK) with a regulatory subunit that brings to mind the mysterious captain in Jules Verne's science fiction novels: NEMO.

The question that had to be answered was how does NEMO activate NF-κB? This is where the work of the Frankfurt biochemists came in. They identified a subdomain of NEMO, called UBAN that binds selectively to a specific type of ubiquitin. This protein is ubiquitous in the cell and has various functions, acting as a multifaceted molecular signal. It can function as a single molecule (monoubiquitin) or in the form of chains (polyubiquitin).

In the scientific journal "Cell", Ivan Dikic and his colleagues report that NEMO specifically binds to linear ubiquitin chains and that this is an essential step for NF-κB activation. This came as a big surprise to the team, since it was previously thought that other types of ubiquitin signals were critical for NEMO-dependent NF-κB activation. "This results in a paradigm change", says Ivan Dikic, "it means, that current knowledge on NF-κB activation and the role of linear ubiquitin chains needs to be updated".

In cooperation with the group of Soichi Wakatsuki, NEMO's structure could be solved. The work demonstrates that the UBAN domain binds to a linear ubiquitin chain according to the key-and-lock-principle. "These new findings not only explain the atomic details of ubiquitin chain selectivity, but can also provide useful insights into developing therapy for targeting the NF-κB pathway", reports Soichi Wakatsuki. Increased activation of the NF-κB pathway is known to be linked to development of different diseases such as cancer and inflammation.

The discovery also has direct medical relevance. "We are happy that this basic scientific discovery may explain the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency", Ivan Dikic points out. Ectodermal dysplasia is a hereditary disease, which affects 1 to 5 children in 10,000 newborn. It causes the skin to be very thin and the perspiratory glands to malfunction. In some cases it is combined with immune deficiency. The molecular defect is a mutation in the NEMO gene, which blocks the activation of the NF-κB pathway in epidermal and immune cells.

This work will be published in the March 20, 2009 issue of the scientific journal Cell.


Story Source:

The above story is based on materials provided by Goethe University Frankfurt. Note: Materials may be edited for content and length.


Cite This Page:

Goethe University Frankfurt. "Paradigm Shift In Immune Response Regulation." ScienceDaily. ScienceDaily, 26 March 2009. <www.sciencedaily.com/releases/2009/03/090319132950.htm>.
Goethe University Frankfurt. (2009, March 26). Paradigm Shift In Immune Response Regulation. ScienceDaily. Retrieved December 19, 2014 from www.sciencedaily.com/releases/2009/03/090319132950.htm
Goethe University Frankfurt. "Paradigm Shift In Immune Response Regulation." ScienceDaily. www.sciencedaily.com/releases/2009/03/090319132950.htm (accessed December 19, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Friday, December 19, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

The Best Tips to Curb Holiday Carbs

The Best Tips to Curb Holiday Carbs

Buzz60 (Dec. 19, 2014) It's hard to resist those delicious but fattening carbs we all crave during the winter months, but there are some ways to stay satisfied without consuming the extra calories. Vanessa Freeman (@VanessaFreeTV) has the details. Video provided by Buzz60
Powered by NewsLook.com
Sierra Leone Bikers Spread the Message to Fight Ebola

Sierra Leone Bikers Spread the Message to Fight Ebola

AFP (Dec. 19, 2014) More than 100 motorcyclists hit the road to spread awareness messages about Ebola. Nearly 7,000 people have now died from the virus, almost all of them in west Africa, according to the World Health Organization. Video provided by AFP
Powered by NewsLook.com
Researchers Test Colombian Village With High Alzheimer's Rates

Researchers Test Colombian Village With High Alzheimer's Rates

AFP (Dec. 19, 2014) In Yarumal, a village in N. Colombia, Alzheimer's has ravaged a disproportionately large number of families. A genetic "curse" that may pave the way for research on how to treat the disease that claims a new victim every four seconds. Duration: 02:42 Video provided by AFP
Powered by NewsLook.com
Double-Amputee Becomes First To Move Two Prosthetic Arms With His Mind

Double-Amputee Becomes First To Move Two Prosthetic Arms With His Mind

Buzz60 (Dec. 19, 2014) A double-amputee makes history by becoming the first person to wear and operate two prosthetic arms using only his mind. Jen Markham has the story. Video provided by Buzz60
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins