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

被引:131
作者
Wang, HW [1 ]
Sharp, TV [1 ]
Koumi, A [1 ]
Koentges, G [1 ]
Boshoff, C [1 ]
机构
[1] UCL, Wolfson Inst Biomed Res, Canc Res UK Viral Oncol Grp, London WC1E 6BT, England
关键词
apoptosis; caspase-3; human survivin; K7; Kaposi's sarcoma-associated herpesvirus;
D O I
10.1093/emboj/21.11.2602
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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).
引用
收藏
页码:2602 / 2615
页数:14
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共 111 条
[101]  
Verdecia MA, 2000, NAT STRUCT BIOL, V7, P602
[102]  
VERHAGEN AM, 2001, GENOME BIOL, V2
[103]   p53: Death star [J].
Vousden, KH .
CELL, 2000, 103 (05) :691-694
[104]   A mutational analysis of the baculovirus inhibitor of apoptosis Op-IAP [J].
Vucic, D ;
Kaiser, WJ ;
Miller, LK .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (51) :33915-33921
[105]   Tumor necrosis factor receptor and Fas signaling mechanisms [J].
Wallach, D ;
Varfolomeev, EE ;
Malinin, NL ;
Goltsev, YV ;
Kovalenko, AV ;
Boldin, MP .
ANNUAL REVIEW OF IMMUNOLOGY, 1999, 17 :331-367
[106]   Identification of the functional regions required for hepatitis D virus replication and transcription by linker-scanning mutagenesis of viral genome [J].
Wang, HW ;
Wu, HL ;
Chen, DS ;
Chen, PJ .
VIROLOGY, 1997, 239 (01) :119-131
[107]   TUMOR-MARKERS IN DIAGNOSIS AND MANAGEMENT [J].
WARNES, TW ;
SMITH, A .
BAILLIERES CLINICAL GASTROENTEROLOGY, 1987, 1 (01) :63-89
[108]   Movement of Bax from the cytosol to mitochondria during apoptosis [J].
Wolter, KG ;
Hsu, YT ;
Smith, CL ;
Nechushtan, A ;
Xi, XG ;
Youle, RJ .
JOURNAL OF CELL BIOLOGY, 1997, 139 (05) :1281-1292
[109]   BH1 AND BH2 DOMAINS OF BCL-2 ARE REQUIRED FOR INHIBITION OF APOPTOSIS AND HETERODIMERIZATION WITH BAX [J].
YIN, XM ;
OLTVAI, ZN ;
KORSMEYER, SJ .
NATURE, 1994, 369 (6478) :321-323
[110]   ch-IAP1, a member of the inhibitor-of-apoptosis protein family, is a mediator of the antiapoptotic activity of the v-Rel oncoprotein [J].
You, MJ ;
Ku, PT ;
Hrdlickova, R ;
Bose, HR .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (12) :7328-7341