Characterization of an anti-apoptotic glycoprotein encoded by Kaposi's sarcoma-associated herpesvirus which resembles a spliced variant of human survivin.
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-DeltaEx3, a splice variant of human survivin that protects cells from apoptosis by an undefined mechanism. Both K7 and survivin-DeltaEx3 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-DeltaEx3 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-DeltaEx3 might function by a similar mechanism to that of K7. We denote K7 as vIAP (viral inhibitor-of-apoptosis protein).
Wang
Hsei-Wei
HW
The Cancer Research UK Viral Oncology Group, Wolfson Institute for Biomedical Research, Cruciform Building, University College London, London WC1E 6BT, UK.
Sharp
Tyson V
TV
Koumi
Andrew
A
Koentges
Georgy
G
Boshoff
Chris
C
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D017209:Apoptosis; D015152:Blotting, Northern; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012984:Software; D013347:Subcellular Fractions / Q000378:metabolism; D000077022:Survivin; D014162:Transfection
C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D018076:DNA, Complementary; D006023:Glycoproteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D005982:Glutathione Transferase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases