Differential cleavage of viral polypeptides by allotypic variants of granzyme B skews immunity to mouse cytomegalovirus
Vivien R Sutton, Christopher Andoniou, Michael G Leeming, Colin M House, Sally Watt, Sandra Verschoor, Annette Ciccone, Ilia Voskoboinik, Mariapia Degli-Esposti, Joseph A Trapani
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | ELSEVIER | Published : 2020
We investigated the molecular basis for the remarkably different survival outcomes of mice expressing different alloforms of the pro-apoptotic serine protease granzyme B to mouse cytomegalovirus infection. Whereas C57BL/6 mice homozygous for granzyme BP (GzmBP/P) raise cytotoxic T lymphocytes that efficiently kill infected cells, those of C57BL/6 mice congenic for the outbred allele (GzmBW/W) fail to kill MCMV-infected cells and died from uncontrolled hepatocyte infection and acute liver failure. We identified subtle differences in how GzmBP and GzmBW activate cell death signalling - both alloforms predominantly activated pro-caspases directly, and cleaved pro-apoptotic Bid poorly. Consequen..View full abstract
The work described here was supported by Program and Project grants to JAT, IV, MD-E and CA from the National Health and Medical Research Council of Australia. JAT is supported through generous philanthropic support as a Rosie Lew Fellow of the Peter Mac Research Foundation.