Differential cleavage of viral polypeptides by allotypic variants of granzyme B skews immunity to mouse cytomegalovirus |
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| Institution: | 1. Department of Agriculture, Medicinal Plants and Drug Research Institute, Shahid Beheshti University, G.C., Evin, 1483963113 Tehran, Iran;2. Imam Khomeini International University, Qazvin, Iran;3. Department of Horticultural Sciences, Faculty of Agriculture and Natural Resources, Arak University, 38156-8-8349 Arak, Iran;1. School of Materials Science and Nanotechnology, Jadavpur University, Kolkata 700032, India;2. Thin Film and Nanoscience Laboratory, Department of Physics, Jadavpur University, Kolkata 700032, India;1. College of Power Engineering, Chongqing University, Chongqing 400044, China;2. Key Laboratory of Low-grade Energy Utilization Technologies and Systems, Ministry of Education of PRC, Chongqing 400044, China;1. Shandong Province Key Laboratory of Laser Polarization and Information Technology, School of Physics and Engineering, Qufu Normal University, 273165 Qufu, People''s Republic of China;2. State Key Laboratory of Functional Materials for Informatics, Laboratory of Nanotechnology, Shanghai Institute of Micro-system and Information Technology, Chinese Academy of Sciences, 200050 Shanghai, People''s Republic of China;3. National Laboratory of Solid State Microstructures, Nanjing University, Nanjing 210093, People''s Republic of China;1. Gene-Marker Laboratory, Department of Agricultural Sciences, Faculty of Agriculture and Life Sciences, PO Box 85084, Lincoln University, Lincoln 7647, Christchurch, New Zealand;2. Faculty of Health and Sport Sciences, Eastern Institute of Technology, Private Bag 1201, Napier 4142, New Zealand;3. Christchurch School of Medicine and Health Sciences, PO Box 4345, Christchurch, New Zealand |
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| Abstract: | 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. Consequently, neither alloform initiated mitochondrial outer membrane permeabilization, or was blocked by Bcl-2, Bcl-XL or co-expression of MCMV proteins M38.5/M41.1, which together stabilize mitochondria by sequestering Bak/Bax. Remarkably, mass spectrometric analysis of proteins from MCMV-infected primary mouse embryonic fibroblasts identified 13 cleavage sites in nine viral proteins (M18, M25, M28, M45, M80, M98, M102, M155, M164) that were cleaved >20-fold more efficiently by either GzmBP or GzmBW. Notably, M18, M28, M45, M80, M98, M102 and M164 were cleaved 20- >100-fold more efficiently by GzmBW, and so, would persist in infected cells targeted by CTLs from GzmBP/P mice. Conversely, M155 was cleaved >100-fold more efficiently by GzmBP, and would persist in cells targeted by CTLs of GzmBW/W mice. M25 was cleaved efficiently by both proteases, but at different sites. We conclude that different susceptibility to MCMV does not result from skewed endogenous cell death pathways, but rather, to as yet uncharacterised MCMV-intrinsic pathways that ultimately inhibit granzyme B-induced cell death. |
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