Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Influenza “Histone Mimic” Suppresses Antiviral Response

16.03.2012
A team of researchers led by scientists at The Rockefeller University has identified a novel mechanism by which influenza interferes with antiviral host response.

The finding, reported in this week’s issue of the journal Nature, shows that the immunosuppressive NS1 protein of the influenza A virus hijacks key regulators of antiviral gene function by mimicking a core component of gene regulating machinery. The results they describe have major implications for our understanding of the biology of seasonal influenza virus and its pathogenesis. This research also suggests a possible target for a new class of antiviral and anti-inflammatory drugs.

The researchers, led by Alexander Tarakhovsky, head of the Laboratory of Immune Cell Epigenetics and Signaling, showed that the NS1 protein of the H3N2 influenza -- the most common strain circulating each flu season -- contains the same sequence of amino acids as the “tail” domain of a DNA packaging protein in humans called histone H3. The histones are present in the cell nucleus and play an important role in gene activation. Chemical modifications of the histone ”tails” allow recruitment of effector proteins that, in turn, determine which genes are switched on or off. Chemical modifications of histones were first identified by Rockefeller scientist Vincent G. Allfrey in the early 1960s. Decades later, Rockefeller University’s C. David Allis proposed the ”histone code” theory that describes the importance of histone tails in regulating a wide array of cellular functions.

“By mimicking the histone H3 tail, the NS1 tail gives the virus access to the core of gene regulating machinery,” says first author Ivan Marazzi, a postdoctoral fellow in the Tarakhovsky lab. “Through this mimicry the virus targets a set of proteins in the nucleus of the infected cells and impairs the anti-viral host cell response.”

Marazzi, together with graduate student Jessica Ho, discovered the ability of NS1 protein to track and target a protein complex called PAF1C, which has been previously studied extensively by Robert G. Roeder’s lab at Rockefeller. Together with Roeder’s lab, the Tarakhovsky lab revealed the ability of NS1 to interfere with the activity of PAF1 complex. This complex turned out to be essential for the expression of the genes that are responsible for antiviral response.

“NS1 is hijacking PAF1C and using its similarity with the H3 ‘tail’ to gain access to a position in the genome that helps the virus to block antiviral genes,” says Ho. “This finding extends the known ability of pathogens to reveal key regulatory processes and to use them for the pathogen’s advantage.”

The current study bears several major implications for influenza research and treatment. The NS1 protein varies from strain to strain. The ”tail” of NS1 appears to be one of the most diverse parts of the NS1 protein. Some flu strains such as H1N1, which was responsible for the 2009 pandemic, do not contain an NS1 “tail” at all. Together with their collaborator, prominent flu researcher Adolfo Garcia-Sastre of Mount Sinai School of Medicine, the Tarakhovsky lab plans to test if diversification of the NS1 “tail” helps the influenza virus to maintain a long-term presence within the human or animal populations. It is also puzzling how the influenza virus, which has no history of integration into animal or human DNA, has “learned” about the functional benefits of the histone “tail.”

Finally, by identifying PAF1C as a NS1 target, the researchers may have found a promising new target for attenuation of inflammatory responses. In collaboration with GlaxoSmithKline, previous efforts of the Tarakhovsky lab in this direction yielded a synthetic “histone mimic” called I-BET. By binding to BET proteins that control inflammatory gene expression, I-BET suppresses inflammation. I-BET and the related compound JQ1, which has been identified by Jay Bradner at the Dana-Farber Cancer Institute at Harvard Medical School, are now considered a new generation of so called “epigenetic” drugs, i.e., drugs that control DNA function without interfering with it directly.

The current discovery is proof and validation of the functional importance of “histone mimicry,” a phenomenon that was first discovered by Srihari Sampath, a Rockefeller M.D.-P.hD. student in Tarakhovsky’s lab. “I was always fascinated by mimicry and even brought an aquarium to my office with the hope of studying mimicry in fish,” says Tarakhovsky. “The aquarium experiment did not work well, but I am glad that I was helped by the flu.”

Joseph Bonner | Newswise Science News
Further information:
http://www.rockefeller.edu

More articles from Health and Medicine:

nachricht Diabetes mellitus: A risk factor for early colorectal cancer
27.05.2020 | Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg

nachricht Ultra-thin fibres designed to protect nerves after brain surgery
27.05.2020 | Martin-Luther-Universität Halle-Wittenberg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Biotechnology: Triggered by light, a novel way to switch on an enzyme

In living cells, enzymes drive biochemical metabolic processes enabling reactions to take place efficiently. It is this very ability which allows them to be used as catalysts in biotechnology, for example to create chemical products such as pharmaceutics. Researchers now identified an enzyme that, when illuminated with blue light, becomes catalytically active and initiates a reaction that was previously unknown in enzymatics. The study was published in "Nature Communications".

Enzymes: they are the central drivers for biochemical metabolic processes in every living cell, enabling reactions to take place efficiently. It is this very...

Im Focus: New double-contrast technique picks up small tumors on MRI

Early detection of tumors is extremely important in treating cancer. A new technique developed by researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from normal tissue. The work is published May 25 in the journal Nature Nanotechnology.

researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from...

Im Focus: I-call - When microimplants communicate with each other / Innovation driver digitization - "Smart Health“

Microelectronics as a key technology enables numerous innovations in the field of intelligent medical technology. The Fraunhofer Institute for Biomedical Engineering IBMT coordinates the BMBF cooperative project "I-call" realizing the first electronic system for ultrasound-based, safe and interference-resistant data transmission between implants in the human body.

When microelectronic systems are used for medical applications, they have to meet high requirements in terms of biocompatibility, reliability, energy...

Im Focus: When predictions of theoretical chemists become reality

Thomas Heine, Professor of Theoretical Chemistry at TU Dresden, together with his team, first predicted a topological 2D polymer in 2019. Only one year later, an international team led by Italian researchers was able to synthesize these materials and experimentally prove their topological properties. For the renowned journal Nature Materials, this was the occasion to invite Thomas Heine to a News and Views article, which was published this week. Under the title "Making 2D Topological Polymers a reality" Prof. Heine describes how his theory became a reality.

Ultrathin materials are extremely interesting as building blocks for next generation nano electronic devices, as it is much easier to make circuits and other...

Im Focus: Rolling into the deep

Scientists took a leukocyte as the blueprint and developed a microrobot that has the size, shape and moving capabilities of a white blood cell. Simulating a blood vessel in a laboratory setting, they succeeded in magnetically navigating the ball-shaped microroller through this dynamic and dense environment. The drug-delivery vehicle withstood the simulated blood flow, pushing the developments in targeted drug delivery a step further: inside the body, there is no better access route to all tissues and organs than the circulatory system. A robot that could actually travel through this finely woven web would revolutionize the minimally-invasive treatment of illnesses.

A team of scientists from the Max Planck Institute for Intelligent Systems (MPI-IS) in Stuttgart invented a tiny microrobot that resembles a white blood cell...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Dresden Nexus Conference 2020: Same Time, Virtual Format, Registration Opened

19.05.2020 | Event News

Aachen Machine Tool Colloquium AWK'21 will take place on June 10 and 11, 2021

07.04.2020 | Event News

International Coral Reef Symposium in Bremen Postponed by a Year

06.04.2020 | Event News

 
Latest News

Black nitrogen: Bayreuth researchers discover new high-pressure material and solve a puzzle of the periodic table

29.05.2020 | Materials Sciences

Argonne researchers create active material out of microscopic spinning particles

29.05.2020 | Materials Sciences

Smart windows that self-illuminate on rainy days

29.05.2020 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>