The immediate early 2 protein of human cytomegalovirus (HCMV) mediates the apoptotic control in HCMV retinitis through up-regulation of the cellular FLICE-inhibitory protein expression.
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.
Chiou
Shih-Hwa
SH
Department of Ophthalmology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan.
Yang
Yi-Ping
YP
Lin
Jung-Chun
JC
Hsu
Chih-Hung
CH
Jhang
Hua-Ci
HC
Yang
Yu-Ting
YT
Lee
Chen-Hsen
CH
Ho
Larry L T
LL
Hsu
Wen-Ming
WM
Ku
Hung-Hai
HH
Chen
Shih-Jen
SJ
Chen
Steve S-L
SS
Chang
Margaret D T
MD
Wu
Cheng-Wen
CW
Juan
Li-Jung
LJ
D017209:Apoptosis / Q000235:genetics*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000032:analysis / Q000235:genetics*; D002478:Cells, Cultured; D017726:Cytomegalovirus Retinitis / Q000235:genetics* / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000032:analysis / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012160:Retina / Q000737:chemistry / Q000378:metabolism / Q000821:virology; D017384:Sequence Deletion; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053222:Fas Ligand Protein; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D015534:Trans-Activators; D019869:Phosphatidylinositol 3-Kinases