Requirement of calmodulin binding by HIV-1 gp160 for enhanced FAS-mediated apoptosis

被引:41
作者
Micoli, KJ
Pan, G
Wu, Y
Williams, JP
Cook, WJ
McDonald, JM
机构
[1] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA
[2] Vet Adm Med Ctr, Birmingham, AL 35233 USA
关键词
D O I
10.1074/jbc.275.2.1233
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
Accelerated apoptosis is one mechanism proposed for the loss of CD4+ T-lymphocytes in human immunodeficiency virus type 1 (HIV-1) infection. The HIV-1 envelope glycoprotein, gp160, contains two C-terminal calmodulin-binding domains. Expression of gp160 in Jurkat T-cells results in increased sensitivity to FAS- and ceramide-mediated apoptosis, The pro-apoptotic effect of gp160 expression is blocked by two calmodulin antagonists, tamoxifen and trifluoperazine. This enhanced apoptosis in response to FAS antibody or C-2-ceramide is associated with activation of caspase 3, a critical mediator of apoptosis, A point mutation in the C-terminal calmodulin-binding domain of gp160 (alanine 835 to tryptophan, A835W) eliminates gp160-dependent enhanced FAS-mediated apoptosis in transiently transfected cells, as well as in vitro calmodulin binding to a peptide corresponding to the C-terminal calmodulin-binding domain of gp160, Stable Tet-off Jurkat cell lines were developed that inducibly express wild type gp160 or gp160A835W, Increasing expression of wild type gp160, but not gp160A835W, correlates with increased calmodulin levels, increased apoptosis, and caspase 3 activation in response to anti-FAS treatment. The data indicate that gp160-enhanced apoptosis is dependent upon calmodulin up-regulation, involves the activation of caspase 3, and requires calmodulin binding to the C-terminal binding domain of gp160.
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页码:1233 / 1240
页数:8
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