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 journalArticle

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 languageEnglish
Article number4670
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

Fingerprint

Toll-Like Receptors
immunity
Cytomegalovirus
Innate Immunity
Antiviral Agents
degradation
lysosomes
proteins
suppressors
Degradation
avoidance
impairment
destabilization
viruses
Virus Latency
surveillance
Viruses
Ubiquitination
Proteins
Lysosomes

All Science Journal Classification (ASJC) codes

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

Cite this

Park, Areum ; Ra, Eun A. ; Lee, Taeyun A. ; Choi, Hyunjin ; Lee, Eunhye ; Kang, Sujin ; Seo, Jun Young ; Lee, Sungwook ; Park, Boyoun. / HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways. In: Nature communications. 2019 ; Vol. 10, No. 1.
@article{df1e47ca770d4215b4805139bfd8ad0d,
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",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41467-019-12641-4",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways. / Park, Areum; Ra, Eun A.; Lee, Taeyun A.; Choi, Hyunjin; Lee, Eunhye; Kang, Sujin; Seo, Jun Young; Lee, Sungwook; Park, Boyoun.

In: Nature communications, Vol. 10, No. 1, 4670, 01.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways

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

PY - 2019/12/1

Y1 - 2019/12/1

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85073168699&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073168699&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-12641-4

DO - 10.1038/s41467-019-12641-4

M3 - Article

C2 - 31604943

AN - SCOPUS:85073168699

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4670

ER -