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Gamma secretase inhibition impairs HCMV replication by reduction of immediate early gene expression at the transcriptional level.

Abstract：

:Due to diverse pathogenic potentials, there is a growing need for anti-HCMV agents. In this study, we show that treatment with DAPT, a γ-secretase inhibitor (GSI), impairs HCMV replication as assessed by a progeny assay based on immunostaining. This effect is not limited to DAPT because other GSIs with different structures and distinct mechanisms of action also exhibit a similar level of inhibitory effects on HCMV viral production, indicating that γ-secretase activity is required for efficient HCMV replication. Western blot and qPCR analyses reveal that DAPT does not interfere with the viral entry process, but reduces expression of the immediate early protein IE1 at the transcriptional level. Furthermore, we exclude the possible involvement of Notch signaling pathway during HCMV replication by showing that expression of the dominant-negative form of MAML1, which disrupts the transactivational ability of Notch intracellular domain (NICD), does not reduce viral particle formation, and that NICD cannot rescue the DAPT-treated outcomes. Taken together, these findings indicate that γ-secretase activity plays an important role in a key step of the HCMV life cycle and γ-secretase inhibition could potentially be used as a novel preventive and therapeutic strategy against HCMV infection and HCMV-related diseases.

journal_name

Antiviral Res

journal_title

Antiviral research

authors

Lee SM,Han D,Kwon M,Noh H,Lee JH,Yoon Y,Cho JY,Ahn JH,Yoon K

doi

10.1016/j.antiviral.2020.104867

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

104867

eissn

0166-3542

issn

1872-9096

pii

S0166-3542(20)30281-3

journal_volume

183

pub_type

杂志文章

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