The herpes simplex virus-1 Us3 protein kinase blocks CD8T cell lysis by preventing the cleavage of Bid by granzyme B.
The Us3 kinase is part of the antiapoptotic arsenal that salvages herpes simplex virus (HSV)-1-infected cells from damage caused by different stimuli. We demonstrate that Us3 protects HSV-1-infected cells from lysis by MHC class I-restricted CD8T cells without affecting antigen presentation. Expression of Us3 was associated with inhibition of caspase activation and reduced cleavage of the proapoptotic protein Bid. Recombinant granzyme B (GrB) failed to cleave Bid in cytosolic extracts from Us3 positive cells, while recombinant Bid served as substrate for Us3 phosphorylation, suggesting that modification of Bid by Us3 blocks its processing by GrB. Our data illustrate a new strategy of viral escape, where modification of a cellular proapoptotic substrate may prevent lysis of the infected cells without affecting other T-cell functions.
Cartier
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Microbiology and Tumor Biology Center, MTC Karolinska Institutet, Box 280, Stockholm S-171 77, Sweden.
Broberg
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Komai
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Henriksson
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Masucci
M G
MG
D017951:Antigen Presentation; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D053804:Granzymes; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008285:Major Histocompatibility Complex; D008856:Microscopy, Fluorescence; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014764:Viral Proteins
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D020169:Caspases