Navigation Links
Shifting forms: Penn study shows how variations of same protein affect immune response
Date:10/15/2010

PHILADELPHIA 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."


'/>"/>

Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

Related biology news :

1. Shifting Sands highlights past, present and future of Maryland coastal bays ecosystem
2. Shifting baselines confound river restoration
3. North Atlantic fish populations shifting as ocean temperatures warm
4. Bacterial ropes tie down shifting Southwest
5. Shifting cellular energy metabolism may help treat cardiovascular disease
6. Long-term study shows effect of climate change on animal diversity
7. £2 million study to reveal workings of dementia genes
8. New study looks to define evangelicals and how they affect polling
9. CU-Boulder study suggests air quality regulations miss key pollutants
10. Researchers study acoustic communication in deep-sea fish
11. Study reveals homeowner perceptions in fire-prone areas
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Shifting forms: Penn study shows how variations of same protein affect immune response
(Date:4/6/2017)... Forecasts by Product Type (EAC), ... End-Use (Transportation & Logistics, Government & Public Sector, Utilities ... Generation Facility, Nuclear Power), Industrial, Retail, Business Organisation (BFSI), ... you looking for a definitive report on the $27.9bn ... ...
(Date:4/4/2017)... 4, 2017   EyeLock LLC , a leader ... United States Patent and Trademark Office (USPTO) has issued ... linking of an iris image with a face image ... the company,s 45 th issued patent. ... timely given the multi-modal biometric capabilities that have recently ...
(Date:3/30/2017)... YORK , March 30, 2017 Trends, ... type (physiological and behavioral), by technology (fingerprint, AFIS, iris ... voice recognition, and others), by end use industry (government ... and immigration, financial and banking, and others), and by ... Europe , Asia Pacific , ...
Breaking Biology News(10 mins):
(Date:10/11/2017)... YORBA LINDA, CA (PRWEB) , ... October 11, ... ... adapted to upregulate any gene in its endogenous context, enabling overexpression experiments and ... activation (CRISPRa) system with small RNA guides is transformative for performing systematic gain-of-function ...
(Date:10/11/2017)... , Oct. 11, 2017  VMS BioMarketing, a leading ... a nationwide oncology Clinical Nurse Educator (CNE) network, which will ... need for communication among health care professionals to enhance the ... nurses, office staff, and other health care professionals to help ... breast cancer. ...
(Date:10/11/2017)... ... October 11, 2017 , ... Singh Biotechnology today announced that ... SBT-100, its novel anti-STAT3 (Signal Transducer and Activator of Transcription 3) B VHH13 ... cross the cell membrane and bind intracellular STAT3 and inhibit its function. Dysregulation ...
(Date:10/10/2017)... ... October 10, 2017 , ... Dr. Bob Harman, founder and ... San Diego Rotary Club. The event entitled “Stem Cells and Their ... 300+ attendees. Dr. Harman, DVM, MPVM was joined by two human doctors: Peter ...
Breaking Biology Technology: