Characterization of an anti-apoptotic glycoprotein encoded by Kaposi's sarcoma-associated herpesvirus which resembles a spliced variant of human survivin

• Published in: The EMBO journal Vol. 21; no. 11; pp. 2602 - 2615
• Main Authors: Wang, Hsei-Wei, Sharp, Tyson V., Koumi, Andrew, Koentges, Georgy, Boshoff, Chris
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 03-06-2002; Blackwell Publishing Ltd; Oxford University Press
• Subjects: Alternative Splicing; Amino Acid Sequence; Apoptosis; Blotting, Northern; Caspase 3; Caspases - metabolism; Cell Line; Chromosomal Proteins, Non-Histone - chemistry; Cloning, Molecular; DNA, Complementary - metabolism; Endoplasmic Reticulum - metabolism; Glutathione Transferase - metabolism; Glycoproteins - metabolism; Herpesvirus 8, Human - genetics; Herpesvirus 8, Human - metabolism; human survivin; Humans; Inhibitor of Apoptosis Proteins; Kaposi's sarcoma-associated herpesvirus; Microscopy, Fluorescence; Microtubule-Associated Proteins; Mitochondria - metabolism; Models, Biological; Models, Molecular; Molecular Sequence Data; Mutation; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Open Reading Frames; Phylogeny; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2 - metabolism; Sarcoma; Sequence Homology, Amino Acid; Software; Subcellular Fractions - metabolism; Transfection
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/21.11.2602

We have investigated the expression and function of a novel protein encoded by open reading frame (ORF) K7 of Kaposi's sarcoma‐associated herpesvirus (KSHV). Computational analyses revealed that K7 is structurally related to survivin‐ΔEx3, a splice variant of human survivin that protects cells from apoptosis by an undefined mechanism. Both K7 and survivin‐ΔEx3 contain a mitochondrial‐targeting sequence, an N‐terminal region of a BIR (baculovirus IAP repeat) domain and a putative BH2 (Bcl‐2 homology)‐like domain. These suggested that K7 is a new viral anti‐apoptotic protein and survivin‐ΔEx3 is its likely cellular homologue. We show that K7 is a glycoprotein, which can inhibit apoptosis and anchor to intracellular membranes where Bcl‐2 resides. K7 does not associate with Bax, but does bind to Bcl‐2 via its putative BH2 domain. In addition, K7 binds to active caspase‐3 via its BIR domain and thus inhibits the activity of caspase‐3. The BH2 domain of K7 is crucial for the inhibition of caspase‐3 activity and is therefore essential for its anti‐apoptotic function. Furthermore, K7 bridges Bcl‐2 and activated caspase‐3 into a protein complex. K7 therefore appears to be an adaptor protein and part of an anti‐apoptotic complex that presents effector caspases to Bcl‐2, enabling Bcl‐2 to inhibit caspase activity. These data also suggest that survivin‐ΔEx3 might function by a similar mechanism to that of K7. We denote K7 as vIAP (viral inhibitor‐of‐apoptosis protein).