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Characterization of an anti‐apoptotic glycoprotein encoded by Kaposi's sarcoma‐associated herpesvirus which resembles a spliced variant of human survivin
Author(s) -
Wang HseiWei,
Sharp Tyson V.,
Koumi Andrew,
Koentges Georgy,
Boshoff Chris
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.11.2602
Subject(s) - biology , survivin , inhibitor of apoptosis , apoptosis , kaposi's sarcoma associated herpesvirus , caspase , microbiology and biotechnology , effector , open reading frame , death domain , cancer research , virology , peptide sequence , gene , genetics , virus , programmed cell death , herpesviridae , viral disease
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).