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

Shih Hwa Chiou, Yi Ping Yang, Jung Chun Lin, Chih Hung Hsu, Hua Ci Jhang, Yu Ting Yang, Chen Hsen Lee, Larry L T Ho, Wen-Ming Hsu, Hung Hai Ku, Shih Jen Chen, Steve S L Chen, Margaret D T Chang, Cheng Wen Wu, Li Jung Juan

Research output: Contribution to journalArticle

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Abstract

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 immunohistochemicaly 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.

Original languageEnglish
Pages (from-to)6199-6206
Number of pages8
JournalJournal of Immunology
Volume177
Issue number9
Publication statusPublished - Nov 1 2006
Externally publishedYes

Fingerprint

CASP8 and FADD-Like Apoptosis Regulating Protein
Immediate-Early Proteins
Cytomegalovirus Retinitis
Cytomegalovirus
Up-Regulation
Fas Ligand Protein
Caspase 8
Retina
CD95 Antigens
Retinitis
Viral Proteins
Blindness
Phosphatidylinositol 3-Kinases
Genetic Promoter Regions
Caspase 3
Acquired Immunodeficiency Syndrome
Nucleotides

ASJC Scopus subject areas

  • Immunology

Cite this

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. / Chiou, Shih Hwa; Yang, Yi Ping; Lin, Jung Chun; Hsu, Chih Hung; Jhang, Hua Ci; Yang, Yu Ting; Lee, Chen Hsen; Ho, Larry L T; Hsu, Wen-Ming; Ku, Hung Hai; Chen, Shih Jen; Chen, Steve S L; Chang, Margaret D T; Wu, Cheng Wen; Juan, Li Jung.

In: Journal of Immunology, Vol. 177, No. 9, 01.11.2006, p. 6199-6206.

Research output: Contribution to journalArticle

Chiou, SH, Yang, YP, Lin, JC, Hsu, CH, Jhang, HC, Yang, YT, Lee, CH, Ho, LLT, Hsu, W-M, Ku, HH, Chen, SJ, Chen, SSL, Chang, MDT, Wu, CW & Juan, LJ 2006, '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', Journal of Immunology, vol. 177, no. 9, pp. 6199-6206.
Chiou, Shih Hwa ; Yang, Yi Ping ; Lin, Jung Chun ; Hsu, Chih Hung ; Jhang, Hua Ci ; Yang, Yu Ting ; Lee, Chen Hsen ; Ho, Larry L T ; Hsu, Wen-Ming ; Ku, Hung Hai ; Chen, Shih Jen ; Chen, Steve S L ; Chang, Margaret D T ; Wu, Cheng Wen ; Juan, Li Jung. / 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. In: Journal of Immunology. 2006 ; Vol. 177, No. 9. pp. 6199-6206.
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abstract = "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 immunohistochemicaly 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.",
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AU - Chiou, Shih Hwa

AU - Yang, Yi Ping

AU - Lin, Jung Chun

AU - Hsu, Chih Hung

AU - Jhang, Hua Ci

AU - Yang, Yu Ting

AU - Lee, Chen Hsen

AU - Ho, Larry L T

AU - Hsu, Wen-Ming

AU - Ku, Hung Hai

AU - Chen, Shih Jen

AU - Chen, Steve S L

AU - Chang, Margaret D T

AU - Wu, Cheng Wen

AU - Juan, Li Jung

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N2 - 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 immunohistochemicaly 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.

AB - 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 immunohistochemicaly 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.

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