An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses
Mosquito-borne flaviviruses such as dengue (DENV) and Zika (ZIKV) cause hundreds of millions of infections annually. The single-stranded RNA genome of flaviviruses is translated into a polyprotein, which is cleaved equally into individual functional proteins. While structural proteins are packaged into progeny virions and released, most of the nonstructural proteins remain intracellular and could become cytotoxic if accumulated over time. However, the mechanism by which nonstructural proteins are maintained at the levels optimal for cellular fitness and viral replication remains unknown. Here, we identified that the ubiquitin E3 ligase HRD1 is essential for flaviviruses infections in both mammalian hosts and mosquitoes. HRD1 directly interacts with flavivirus NS4A and ubiquitylates a conserved lysine residue for ER-associated degradation. This mechanism avoids excessive accumulation of NS4A, which otherwise interrupts the expression of processed flavivirus proteins in the ER. Furthermore, a small-molecule inhibitor of HRD1 named LS-102 effectively interrupts DENV2 infection in both mice and Aedes aegypti mosquitoes, and significantly disturbs DENV transmission from the infected hosts to mosquitoes owing to reduced viremia. Taken together, this study demonstrates that flaviviruses have evolved a sophisticated mechanism to exploit the ubiquitination system to balance the homeostasis of viral proteins for their own advantage and provides a potential therapeutic target to interrupt flavivirus infection and transmission.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 16 vom: 16. Apr., Seite e2317978121 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wu, Linjuan [VerfasserIn] |
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| Links: |
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| Themen: |
EC 6.- |
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| Anmerkungen: |
Date Completed 11.04.2024 Date Revised 26.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2317978121 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370824105 |
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| 100 | 1 | |a Wu, Linjuan |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Mosquito-borne flaviviruses such as dengue (DENV) and Zika (ZIKV) cause hundreds of millions of infections annually. The single-stranded RNA genome of flaviviruses is translated into a polyprotein, which is cleaved equally into individual functional proteins. While structural proteins are packaged into progeny virions and released, most of the nonstructural proteins remain intracellular and could become cytotoxic if accumulated over time. However, the mechanism by which nonstructural proteins are maintained at the levels optimal for cellular fitness and viral replication remains unknown. Here, we identified that the ubiquitin E3 ligase HRD1 is essential for flaviviruses infections in both mammalian hosts and mosquitoes. HRD1 directly interacts with flavivirus NS4A and ubiquitylates a conserved lysine residue for ER-associated degradation. This mechanism avoids excessive accumulation of NS4A, which otherwise interrupts the expression of processed flavivirus proteins in the ER. Furthermore, a small-molecule inhibitor of HRD1 named LS-102 effectively interrupts DENV2 infection in both mice and Aedes aegypti mosquitoes, and significantly disturbs DENV transmission from the infected hosts to mosquitoes owing to reduced viremia. Taken together, this study demonstrates that flaviviruses have evolved a sophisticated mechanism to exploit the ubiquitination system to balance the homeostasis of viral proteins for their own advantage and provides a potential therapeutic target to interrupt flavivirus infection and transmission | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Zhang, Liming |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Shengyong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Cai |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Yibin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Penghua |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Gong |e verfasserin |4 aut | |
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