The Us3 protein kinase of herpes simplex virus 1 blocks apoptosis and induces phosporylation of the Bcl-2 family member Bad.
Viruses have evolved different strategies to interfere with apoptotic pathways in order to halt cellular responses to infection. The herpes simplex virus 1 (HSV-1) Us3 open-reading frame encodes a serine/threonine protein kinase that participates in the inhibition of apoptosis induced by virus infection and other stress agents. Previous studies have shown that Us3 counteracts the virus-induced activation of caspase-3 by acting at a premitochondrial stage. Using stable transfectants that express Us3 under the control of constitutive or inducible promoters we demonstrate that apoptosis induced by treatment with anti-Fas antibody and sorbitol is blocked when Us3 is expressed at levels comparable to those achieved during virus infection. Expression of Us3 correlated with phosphorylation of Bad, a BH3-only proapoptotic Bcl-2 family member that is also a target for growth factor-induced cellular kinases. Bad was phosphorylated by Us3 in in vitro kination assays. These results point to a strategy for viral inhibition of apoptosis based on functional inactivation of a critical component of the cellular death machinery.
Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Anna
A
Cartier
Tomoaki
T
Komai
Maria G
MG
Masucci
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D053938:DNA Fragmentation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006561:Herpes Simplex / Q000201:enzymology* / Q000503:physiopathology; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000472:pathogenicity; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013012:Sorbitol / Q000494:pharmacology; D014709:Vero Cells; D014764:Viral Proteins; D051025:bcl-Associated Death Protein; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism
D000906:Antibodies; C494819:BAD protein, human; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins; D051025:bcl-Associated Death Protein; D019014:fas Receptor; D013012:Sorbitol; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1