| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
,
,¶
* Department of Ophthalmology and
Department of Medical Research and Education, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, Republic of China;
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China;
National Research Institute of Chinese Medicine, Taipei, Taiwan, Republic of China;
¶ Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, Republic of China;
|| Genomics Research Center, Academia Sinica, Taipei, Taiwan, Republic of China;
# Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan, Republic of China;
** Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China; and
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
Human CMV (HCMV) is a widespread human pathogen that causes blindness by inducing retinitis in AIDS patients. Previously, we showed that viral immediate early 2 (IE2) protein may allow HCMV to evade the immune control by killing the Fas receptor-positive T lymphocytes attracted to the infected retina with increased secretion of Fas ligand (FasL). In this study, we further demonstrate that the secreted FasL also kills uninfected Fas-rich bystander retinal cells and that IE2 simultaneously protects the infected cells from undergoing apoptotic death, in part, by activating the expression of cellular FLIP (c-FLIP), an antiapoptotic molecule that blocks the direct downstream executer caspase 8 of the FasL/Fas pathway. c-FLIP induction requires the N-terminal 98 residues of IE2 and the c-FLIP promoter region spanning nucleotides –978 to –696. In vivo association of IE2 to this region, IE2-specific c-FLIP activation, and decrease of FasL-up-regulated activities of caspases 8 and 3 were all demonstrated in HCMV-infected human retinal cells. Moreover, c-FLIP up-regulation by IE2 appeared to involve PI3K and might also render cells resistant to TRAIL-mediated death. Finally, enhanced c-FLIP signals were immunohistochemically detected in IE-positive cells in the HCMV-infected lesions of the human retina. Taken together, these data demonstrate specific activation of c-FLIP by HCMV IE2 and indicate a novel role for c-FLIP in the pathogenesis of HCMV retinitis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Science Council and the Academia Sinica (to S.-H.C., W.-M.H., S.S.-L.C., C.-W.W., and L.-J.J.) and the National Health Research Institutes of Taiwan (to C.-W.W. and L.-J.J.).
2 Address correspondence and reprint requests to Dr. Li-Jung Juan, Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan, Republic of China; E-mail address: ljjuan{at}gate.sinica.edu.tw or Dr. Cheng-Wen Wu, Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, Republic of China; E-mail address: ken{at}nhri.org.tw
3 Y.-P.Y. and J.-C.L. contributed equally to this work.
4 Abbreviations used in this paper: HCMV, human CMV; IE, immediate early; IE2, IE protein 2; CBP, CREB binding protein; RPE, retinal pigment epithelium; FasL, Fas ligand; HRPE, human RPE; c-FLIP, cellular FLIP; c-FLIPL, c-FLIP long form; c-FLIPS, c-FLIP short form; siRNA, short-interfering RNA; MOI, multiplicity of infection; MIE, major IE gene; ChIP, chromatin immunoprecipitation; DAPI, 4',6'-diamidino-2-phenylindole; IE1, IE protein 1; pi, postinfection; CHX, cycloheximide.
This article has been cited by other articles:
|
|
 |
|
  M. C.-J. Cheeran, J. R. Lokensgard, and M. R. Schleiss Neuropathogenesis of Congenital Cytomegalovirus Infection: Disease Mechanisms and Prospects for Intervention Clin. Microbiol. Rev., January 1, 2009; 22(1): 99 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mandron, H. Martin, B. Bonjean, J. Lule, E. Tartour, and C. Davrinche Dendritic cell-induced apoptosis of human cytomegalovirus-infected fibroblasts promotes cross-presentation of pp65 to CD8+ T cells J. Gen. Virol., January 1, 2008; 89(1): 78 - 86. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zhang, B. Marshall, and S. S. Atherton Murine Cytomegalovirus Infection and Apoptosis in Organotypic Retinal Cultures Invest. Ophthalmol. Vis. Sci., January 1, 2008; 49(1): 295 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-L. Lin, S.-H. Chiou, C.-W. Wu, W.-B. Lin, L.-H. Chen, Y.-P. Yang, M.-L. Tsai, Y.-H. Uen, J.-P. Liou, and C.-W. Chi Combretastatin A4-Induced Differential Cytotoxicity and Reduced Metastatic Ability by Inhibition of AKT Function in Human Gastric Cancer Cells J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 365 - 373. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
