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|
University of Pennsylvania School of Medicine