Endoplasmic Reticulum Protein SCAP Inhibits Dengue Virus NS2B3 Protease by Suppressing Its K27-Linked Polyubiquitylation
Copyright © 2017 American Society for Microbiology..
Dengue viruses (DENVs) are an emerging threat to global public health. The NS2B3 protease complex of DENV has recently been shown to cleave the antiviral protein STING and thereby subvert the innate immune signaling to facilitate virus replication. Whether host cells have a mechanism to counteract this virus-mediated immunosuppression is unclear. We discovered that the K27-linked polyubiquitination of NS3 protein facilitates its recruitment of NS2B, the formation of NS2B3, and consequently the enhanced cleavage of STING. However, an endoplasmic reticulum (ER) protein, SCAP, through binding to NS2B protein, inhibits the ubiquitination of NS3, rendering NS2B3 protease incapable of binding and cleaving STING. Importantly, ectopic expression of SCAP impaired DENV infection, whereas silencing of SCAP potentiated DENV infection. Collectively, this study uncovered a novel function of SCAP of counteracting the inhibitory action of DENV NS2B3 protease on STING signaling, suggesting that modulation of SCAP levels may have therapeutic implications.IMPORTANCE This study reports the first ubiquitylation target protein in DENV, the NS3 protein, and the unique role of K27-linked polyubiquitylation in NS3's ability to recruit NS2B and formation of the NS2B3 protease complex. Additionally, this study identified novel functions of the ER protein SCAP: one is to compete with NS2B for binding to STING, and the other is to inhibit the ubiquitination of NS3. Both of these functions protect STING from being cleaved by the NS2B3 protease and thus contribute to host antiviral response.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:91 |
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| Enthalten in: |
Journal of virology - 91(2017), 9 vom: 01. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Heng [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.05.2017 Date Revised 14.12.2020 published: Electronic-Print ErratumIn: J Virol. 2018 Feb 26;92 (6):. - PMID 29483287 Citation Status MEDLINE |
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| doi: |
10.1128/JVI.02234-16 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM269211012 |
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| 100 | 1 | |a Liu, Heng |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Endoplasmic Reticulum Protein SCAP Inhibits Dengue Virus NS2B3 Protease by Suppressing Its K27-Linked Polyubiquitylation |
| 264 | 1 | |c 2017 | |
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| 500 | |a Date Completed 15.05.2017 | ||
| 500 | |a Date Revised 14.12.2020 | ||
| 500 | |a published: Electronic-Print | ||
| 500 | |a ErratumIn: J Virol. 2018 Feb 26;92 (6):. - PMID 29483287 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2017 American Society for Microbiology. | ||
| 520 | |a Dengue viruses (DENVs) are an emerging threat to global public health. The NS2B3 protease complex of DENV has recently been shown to cleave the antiviral protein STING and thereby subvert the innate immune signaling to facilitate virus replication. Whether host cells have a mechanism to counteract this virus-mediated immunosuppression is unclear. We discovered that the K27-linked polyubiquitination of NS3 protein facilitates its recruitment of NS2B, the formation of NS2B3, and consequently the enhanced cleavage of STING. However, an endoplasmic reticulum (ER) protein, SCAP, through binding to NS2B protein, inhibits the ubiquitination of NS3, rendering NS2B3 protease incapable of binding and cleaving STING. Importantly, ectopic expression of SCAP impaired DENV infection, whereas silencing of SCAP potentiated DENV infection. Collectively, this study uncovered a novel function of SCAP of counteracting the inhibitory action of DENV NS2B3 protease on STING signaling, suggesting that modulation of SCAP levels may have therapeutic implications.IMPORTANCE This study reports the first ubiquitylation target protein in DENV, the NS3 protein, and the unique role of K27-linked polyubiquitylation in NS3's ability to recruit NS2B and formation of the NS2B3 protease complex. Additionally, this study identified novel functions of the ER protein SCAP: one is to compete with NS2B for binding to STING, and the other is to inhibit the ubiquitination of NS3. Both of these functions protect STING from being cleaved by the NS2B3 protease and thus contribute to host antiviral response | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a K27-polyubiquitin | |
| 650 | 4 | |a NS2B3 | |
| 650 | 4 | |a SCAP | |
| 650 | 4 | |a STING | |
| 650 | 4 | |a dengue virus | |
| 650 | 4 | |a innate immunity | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a NS2B protein, flavivirus |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a SREBP cleavage-activating protein |2 NLM | |
| 650 | 7 | |a STING1 protein, human |2 NLM | |
| 650 | 7 | |a Viral Nonstructural Proteins |2 NLM | |
| 650 | 7 | |a Polyubiquitin |2 NLM | |
| 650 | 7 | |a 120904-94-1 |2 NLM | |
| 650 | 7 | |a NS3 protease, dengue virus |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 650 | 7 | |a Serine Endopeptidases |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 700 | 1 | |a Zhang, Lele |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Senlin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Huansha |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Zanxian |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Xia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chen |e verfasserin |4 aut | |
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