Interferon Antagonism of Epstein–Barr Virus Tegument Proteins
The Epstein–Barr virus (EBV) successfully infects 95% of all adults but causes Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, nasopharyngeal carcinoma or other malignancies in only a small subset of infected individuals. The virus must have developed effective viral countermeasures to ev...
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doaj-fac633e30a7d4e858055bc53d15c62c52020-11-25T03:16:30ZengMDPI AGProceedings2504-39002020-06-0150747410.3390/proceedings2020050074Interferon Antagonism of Epstein–Barr Virus Tegument ProteinsWai-Yan Lui0Sonia Jangra1Kit-San Yuen2Michael George Botelho3Dong-Yan Jin4School of Biomedical Sciences, The University of Hong Kong, 999077 Pokfulam, Hong Kong, ChinaFaculty of Dentistry, The University of Hong Kong, 999077 Sai Ying Pun, Hong Kong, ChinaSchool of Biomedical Sciences, The University of Hong Kong, 999077 Pokfulam, Hong Kong, ChinaFaculty of Dentistry, The University of Hong Kong, 999077 Sai Ying Pun, Hong Kong, ChinaSchool of Biomedical Sciences, The University of Hong Kong, 999077 Pokfulam, Hong Kong, ChinaThe Epstein–Barr virus (EBV) successfully infects 95% of all adults but causes Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, nasopharyngeal carcinoma or other malignancies in only a small subset of infected individuals. The virus must have developed effective viral countermeasures to evade host innate immunity. In this study, we performed functional screens to identify EBV-encoded interferon (IFN) antagonists. Several tegument proteins were found to be potent suppressors of IFN production and/or signaling. The large tegument protein and deubiquitinase BPLF1 antagonized type I IFN production induced by DNA sensors cGAS and STING or RNA sensors RIG-I and MAVS. BPLF1’s ability to suppress innate immune signaling required its deubiquitinase activity. BPLF1 functioned as a catalytically active deubiquitinase for both K63- and K48-linked ubiquitin chains on STING and TBK1, with no ubiquitin linkage specificity. Induced expression of BPLF1 in EBV-infected cells through CRISPRa led to effective suppression of innate DNA and RNA sensing. Another EBV tegument protein, BGLF2, was found to suppress JAK-STAT signaling. This suppression was ascribed to more pronounced K48-linked polyubiquitination and proteasomal degradation of BGLF2-associated STAT2. In addition, BGLF2 also recruited tyrosine phosphatase SHP1 to inhibit tyrosine phosphorylation of JAK1 and STAT1. A BGLF2-deficient EBV activated type I IFN signaling more robustly. Taken together, we characterized the IFN antagonism of EBV tegument proteins BPLF1 and BGLF2, which modulate ubiquitination of key transducer proteins to counteract type I IFN production and signaling in host cells. Supported by HMRF 17160822, HMRF 18170942, and RGC C7027-16G.https://www.mdpi.com/2504-3900/50/1/74Epstein-Barr virustype I interferonJAK-STAT |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wai-Yan Lui Sonia Jangra Kit-San Yuen Michael George Botelho Dong-Yan Jin |
spellingShingle |
Wai-Yan Lui Sonia Jangra Kit-San Yuen Michael George Botelho Dong-Yan Jin Interferon Antagonism of Epstein–Barr Virus Tegument Proteins Proceedings Epstein-Barr virus type I interferon JAK-STAT |
author_facet |
Wai-Yan Lui Sonia Jangra Kit-San Yuen Michael George Botelho Dong-Yan Jin |
author_sort |
Wai-Yan Lui |
title |
Interferon Antagonism of Epstein–Barr Virus Tegument Proteins |
title_short |
Interferon Antagonism of Epstein–Barr Virus Tegument Proteins |
title_full |
Interferon Antagonism of Epstein–Barr Virus Tegument Proteins |
title_fullStr |
Interferon Antagonism of Epstein–Barr Virus Tegument Proteins |
title_full_unstemmed |
Interferon Antagonism of Epstein–Barr Virus Tegument Proteins |
title_sort |
interferon antagonism of epstein–barr virus tegument proteins |
publisher |
MDPI AG |
series |
Proceedings |
issn |
2504-3900 |
publishDate |
2020-06-01 |
description |
The Epstein–Barr virus (EBV) successfully infects 95% of all adults but causes Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, nasopharyngeal carcinoma or other malignancies in only a small subset of infected individuals. The virus must have developed effective viral countermeasures to evade host innate immunity. In this study, we performed functional screens to identify EBV-encoded interferon (IFN) antagonists. Several tegument proteins were found to be potent suppressors of IFN production and/or signaling. The large tegument protein and deubiquitinase BPLF1 antagonized type I IFN production induced by DNA sensors cGAS and STING or RNA sensors RIG-I and MAVS. BPLF1’s ability to suppress innate immune signaling required its deubiquitinase activity. BPLF1 functioned as a catalytically active deubiquitinase for both K63- and K48-linked ubiquitin chains on STING and TBK1, with no ubiquitin linkage specificity. Induced expression of BPLF1 in EBV-infected cells through CRISPRa led to effective suppression of innate DNA and RNA sensing. Another EBV tegument protein, BGLF2, was found to suppress JAK-STAT signaling. This suppression was ascribed to more pronounced K48-linked polyubiquitination and proteasomal degradation of BGLF2-associated STAT2. In addition, BGLF2 also recruited tyrosine phosphatase SHP1 to inhibit tyrosine phosphorylation of JAK1 and STAT1. A BGLF2-deficient EBV activated type I IFN signaling more robustly. Taken together, we characterized the IFN antagonism of EBV tegument proteins BPLF1 and BGLF2, which modulate ubiquitination of key transducer proteins to counteract type I IFN production and signaling in host cells. Supported by HMRF 17160822, HMRF 18170942, and RGC C7027-16G. |
topic |
Epstein-Barr virus type I interferon JAK-STAT |
url |
https://www.mdpi.com/2504-3900/50/1/74 |
work_keys_str_mv |
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