Proteolytic Maturation of Perforin: Determining the Requirements for Cytotoxic Function
Kimberly Risma MD, PhD
Cincinnati Children’s Hospital Medical Center – Cincinnati, Ohio USA
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The immune system utilizes killer lymphocytes to eliminate virally-infected cells and tumor cells from the body by secreting two proteins that work together to eliminate abnormal cells: perforin and granzyme B. Perforin “delivers” the lethal weapon, granzyme B, to the targeted cell by a mechanism that is not clearly defined, but may involve formation of a pore. When perforin expression and/or function are defective due to a mutation in the gene, affected children are at risk for death from a severe inflammatory disease called hemophagocytic lymphohistiocytosis (HLH). When mutations in the perforin gene have been described in children and adults, some of them are disease-causing, while others may not actually cause HLH. We have been eager to determine why some perforin mutations lead to HLH, while others lead to milder clinical disorders or no symptoms at all.
We and others have shown that the perforin protein is processed from a precursor form to a mature form that is stored inside the cell. Some mutations interfere with this processing step, but new data suggest that the processing may not be an absolute requirement for the function of perforin. The focus of this proposal is to define how perforin processing impacts perforin secretion and function. This information will help us to understand why some mutations in perforin lead to later onset disease.