HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways

Areum Park; Eun A. Ra; Taeyun A. Lee; Hyunjin Choi; Eunhye Lee; Sujin Kang; Jun Young Seo; Sungwook Lee; Boyoun Park

doi:10.1038/s41467-019-12641-4

HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways

Areum Park, Eun A. Ra, Taeyun A. Lee, Hyunjin Choi, Eunhye Lee, Sujin Kang, Jun Young Seo, Sungwook Lee, Boyoun Park

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

The mechanisms by which many human cytomegalovirus (HCMV)-encoded proteins help the virus to evade immune surveillance remain poorly understood. In particular, it is unknown whether HCMV proteins arrest Toll-like receptor (TLR) signaling pathways required for antiviral defense. Here, we report that US7 and US8 as key suppressors that bind both TLR3 and TLR4, facilitating their destabilization by distinct mechanisms. US7 exploits the ER-associated degradation components Derlin-1 and Sec61, promoting ubiquitination of TLR3 and TLR4. US8 not only disrupts the TLR3-UNC93B1 association but also targets TLR4 to the lysosome, resulting in rapid degradation of the TLR. Accordingly, a mutant HCMV lacking the US7-US16 region has an impaired ability to hinder TLR3 and TLR4 activation, and the impairment is reversed by the introduction of US7 or US8. Our findings reveal an inhibitory effect of HCMV on TLR signaling, which contributes to persistent avoidance of the host antiviral response to achieve viral latency.

Original language	English
Article number	4670
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12641-4
Publication status	Published - 2019 Dec 1

Bibliographical note

Funding Information:
This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future planning (NRF-2016R1A5A1010764 and NRF-2017R1E1A1A01074135).

Funding Information:
S.L. was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07048930) and a research grant from the National Cancer Center of Korea (NCC-1710210). A.P., E.A.R., H.J.C., T.A.L., E.L., and S.K. were supported by the Brain Korea (BK21) PLUS Program.

Publisher Copyright:
© 2019, The Author(s).

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways",

abstract = "The mechanisms by which many human cytomegalovirus (HCMV)-encoded proteins help the virus to evade immune surveillance remain poorly understood. In particular, it is unknown whether HCMV proteins arrest Toll-like receptor (TLR) signaling pathways required for antiviral defense. Here, we report that US7 and US8 as key suppressors that bind both TLR3 and TLR4, facilitating their destabilization by distinct mechanisms. US7 exploits the ER-associated degradation components Derlin-1 and Sec61, promoting ubiquitination of TLR3 and TLR4. US8 not only disrupts the TLR3-UNC93B1 association but also targets TLR4 to the lysosome, resulting in rapid degradation of the TLR. Accordingly, a mutant HCMV lacking the US7-US16 region has an impaired ability to hinder TLR3 and TLR4 activation, and the impairment is reversed by the introduction of US7 or US8. Our findings reveal an inhibitory effect of HCMV on TLR signaling, which contributes to persistent avoidance of the host antiviral response to achieve viral latency.",

author = "Areum Park and Ra, {Eun A.} and Lee, {Taeyun A.} and Hyunjin Choi and Eunhye Lee and Sujin Kang and Seo, {Jun Young} and Sungwook Lee and Boyoun Park",

note = "Funding Information: This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future planning (NRF-2016R1A5A1010764 and NRF-2017R1E1A1A01074135). Funding Information: S.L. was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07048930) and a research grant from the National Cancer Center of Korea (NCC-1710210). A.P., E.A.R., H.J.C., T.A.L., E.L., and S.K. were supported by the Brain Korea (BK21) PLUS Program. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - Park, Areum

AU - Ra, Eun A.

AU - Lee, Taeyun A.

AU - Choi, Hyunjin

AU - Lee, Eunhye

AU - Kang, Sujin

AU - Seo, Jun Young

AU - Lee, Sungwook

AU - Park, Boyoun

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PY - 2019/12/1

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N2 - The mechanisms by which many human cytomegalovirus (HCMV)-encoded proteins help the virus to evade immune surveillance remain poorly understood. In particular, it is unknown whether HCMV proteins arrest Toll-like receptor (TLR) signaling pathways required for antiviral defense. Here, we report that US7 and US8 as key suppressors that bind both TLR3 and TLR4, facilitating their destabilization by distinct mechanisms. US7 exploits the ER-associated degradation components Derlin-1 and Sec61, promoting ubiquitination of TLR3 and TLR4. US8 not only disrupts the TLR3-UNC93B1 association but also targets TLR4 to the lysosome, resulting in rapid degradation of the TLR. Accordingly, a mutant HCMV lacking the US7-US16 region has an impaired ability to hinder TLR3 and TLR4 activation, and the impairment is reversed by the introduction of US7 or US8. Our findings reveal an inhibitory effect of HCMV on TLR signaling, which contributes to persistent avoidance of the host antiviral response to achieve viral latency.

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HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways

Abstract

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