Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Shifting forms: Penn study shows how variations of same protein affect immune response

18.10.2010
Implications for autoimmune and neurological diseases

How a T cell decides to make protein X, Y, or Z can have profound effects for fighting foreign invaders or staving off dire autoimmune reactions. Researchers at the University of Pennsylvania School of Medicine have identified the steps that control how different forms of an immune cell protein called CD45, which is critical for activating the immune system when faced with pathogens, are controlled in the arc of a body's immune response.

The shift between different forms of CD45 helps T cells function properly and also prevents hyperactivity, which could lead to the body's own immune system attacking itself. Knowing precisely how this shifting system works has implications for understanding autoimmune and neurological diseases.

"We have identified a new paradigm for the regulation of a process called alternative splicing, which allows for a single gene to code for multiple variations of one type of protein," says Kristen W. Lynch, PhD, associate professor of Biochemistry and Biophysics. This study appeared in an October issue of Molecular Cell.

CD45, a receptor protein that sits on the surface of T cells, is essential for immunity, for example, severe combined immune deficiency (SCID), also known as "bubble boy" syndrome, is caused by the absence of CD45.

Normal CD45 comes in five forms, all different lengths. In resting T cells, longer forms of CD45 messenger RNA (mRNA) and protein predominate, but in activated cells, the shorter form of CD45 mRNA is most abundant. "There is a spectrum of forms that shift toward full length in resting cells and towards the shorter form in activated cells," says Lynch. Messenger RNA contains the chemical blueprint for how to make a protein.

"We knew that a protein called PSF was required for splicing out parts of CD45 RNA to make the different forms," says Lynch. Lynch and post-doctoral fellow Florian Heyd, PhD have shown that there are additional critical components to the system that control the relative levels of the five forms of CD45 mRNA.

The first component that they identified is that another molecule called glycogen synthase kinase 3 (GSK3) found in resting T cells adds a phosphate molecule to polypyrimidine-tract binding protein-associated splicing factor (PSF). The phosphorylated PSF is then sequestered in a large protein complex by the third molecule called TRAP150. When PSF stays in this complex, the longer forms of CD45 predominate, and the T cell is ready to respond to foreign invaders. After a response, PSF loses its phosphates, and is released from TRAP150. As a consequence, PSF is then free to form the shortened forms of CD45 mRNA, which helps return the immune response to a resting state.

Splicing of CD45 mRNA involves recognition by PSF of a short length of RNA sequence called the exonic splicing silencer (ESS). Some variations within the ESS sequence are associated with autoimmune disease, especially multiple sclerosis. "We suspect that there are other spliced genes in T cells that follow the same path as CD45, and we are directing current efforts to identify them," said Lynch.

GSK3, a critical element in T cell activation, is important in other cell types and in other signaling pathways: It has been linked to the development of tauopathies, a group of neuronal diseases that includes Alzheimer's disease and Parkinson's disease. GSK3 is the focus of a search for drugs that might affect these and other diseases. For example, lithium is currently used to treat bipolar disorder by inactivating GSK3 in brain cells.

"Known and potential GSK3 inhibitors may also affect the health of the immune system," notes Lynch. "This emphasizes the importance of better understanding the variety of functions of GSK3 in the body."

This study was funded by a grant from the National Institute of General Medical Science and a fellowship from the Deutsche Forschungsgemeinschaft.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $3.6 billion enterprise.

Penn's School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools, and is consistently among the nation's top recipients of funding from the National Institutes of Health, with $367.2 million awarded in the 2008 fiscal year.

Penn Medicine's patient care facilities include:

The Hospital of the University of Pennsylvania – the nation's first teaching hospital, recognized as one of the nation's top 10 hospitals by U.S. News & World Report.

Penn Presbyterian Medical Center – named one of the top 100 hospitals for cardiovascular care by Thomson Reuters for six years.

Pennsylvania Hospital – the nation's first hospital, founded in 1751, nationally recognized for excellence in orthopaedics, obstetrics & gynecology, and psychiatry & behavioral health.

Additional patient care facilities and services include Penn Medicine at Rittenhouse, a Philadelphia campus offering inpatient rehabilitation and outpatient care in many specialties; as well as a primary care provider network; a faculty practice plan; home care and hospice services; and several multispecialty outpatient facilities across the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2009, Penn Medicine provided $733.5 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Studies and Analyses:

nachricht Europe’s Demographic Future. Where the Regions Are Heading after a Decade of Crises
10.08.2017 | Berlin-Institut für Bevölkerung und Entwicklung

nachricht Scientists reveal source of human heartbeat in 3-D
07.08.2017 | University of Manchester

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>