Human Cytomegalovirus UL23 Attenuates Signal Transducer and Activator of Transcription 1 Phosphorylation and Type I Interferon Response.

Linyuan Feng,Xiaotian Li,Wanwei Li,Xingyuan Wu,Xiaoping Yang,Jianguo Wu,Hongjian Li,Yanhong Ran

doi:10.3389/fmicb.2021.692515

Linyuan Feng, Xiaotian Li + Show 6 more

Open Access

https://doi.org/10.3389/fmicb.2021.692515

Copy DOI

Journal: Frontiers in microbiology	Publication Date: Jul 9, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: Jinan University

Abstract

Human cytomegalovirus (HCMV), the human beta-herpesvirus, can cause severe syndromes among both immunocompromised adult patients and newborns. Type I interferon (IFN-I) exerts an important effect to resist infections caused by viruses such as HCMV, while IFN evasion may serve as a key determining factor for viral dissemination and disease occurrence within hosts. In this study, UL23, a tegument protein of HCMV, was confirmed to be a key factor for negatively regulating the type I IFN immune response. A detailed analysis indicated that the viral UL23 protein increases the IFN-I antiviral resistance during HCMV infections. Furthermore, UL23 was shown to significantly reduce the levels of IFN-stimulated genes (ISGs) and promoter activity of IFN-I-stimulated response element. Mechanically, UL23 was discovered to impair the signal transducer and activator of transcription 1 (STAT1) phosphorylation, although it was not found to affect phosphorylation and expression of STAT2, Janus activated kinase 1, or tyrosine kinase 2, which are associated with IFN-I signal transduction pathway. Additionally, a significantly reduced nuclear expression of STAT1 but not of IFN regulatory factor 9 or STAT2 was observed. Findings of this study indicate that HCMV UL23 is a viral antagonist that acts against the cellular innate immunity and reveal a possible novel effect of UL23 on IFN-I signaling.

Highlights

Human cytomegalovirus (HCMV), the human beta-herpesvirus, can induce severe syndromes among immunocompromised adult populations and newborns, such as HIV-infected populations and organ transplant recipients (Sweet, 1999; Hommes et al, 2004; Steininger, 2007; Cheeran et al, 2009)
We previously reported that the HCMV tegument protein, UL23, blocks antiviral type II interferons (IFN-II) responses through binding to N-Myc interactor protein (Nmi) in the human body (Feng et al, 2018)
These results indicated that the IFN-β susceptibility of HCMV UL23 virus increased relative to HCMV Towne virus

Summary

Introduction

Human cytomegalovirus (HCMV), the human beta-herpesvirus, can induce severe syndromes among immunocompromised adult populations and newborns, such as HIV-infected populations and organ transplant recipients (Sweet, 1999; Hommes et al, 2004; Steininger, 2007; Cheeran et al, 2009). Type I interferons (IFN-I), like IFN-β, account for the critical cytokines associated with immune surveillance that confer congenital immunity to resist viral infection (Platanias, 2005; Schoggins, 2019). IFNs can bind to corresponding cell receptors and can activate the signal transduction pathways in cells. STAT1 and STAT2 can form the heterotrimeric transcription factor (TF) by binding to IFN regulatory factor 9 (IRF9), which has been called the IFN-stimulated gene factor 3 (ISGF3) complex (Platanias, 2005; Bonjardim et al, 2009). ISGF3 is subjected to nuclear translocation, followed by binding to the IFNstimulated response elements (ISREs) within DNA for driving diverse interferon-stimulated genes (ISGs) transcription, most of which can exert antiviral effects (Schneider et al, 2014; Platanitis et al, 2019)

Methods

Results

Conclusion