The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection
Summary: Although flaviviruses co-opt the function of the host endoplasmic reticulum (ER) membrane protein complex (EMC) during infection, a mechanistic explanation for this observation remains unclear. Here, we show that the EMC promotes biogenesis of dengue virus (DENV) and Zika virus (ZIKV) non-s...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719305248 |
| _version_ | 1819156248902238208 |
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| author | David L. Lin Takamasa Inoue Yu-Jie Chen Aaron Chang Billy Tsai Andrew W. Tai |
| author_facet | David L. Lin Takamasa Inoue Yu-Jie Chen Aaron Chang Billy Tsai Andrew W. Tai |
| author_sort | David L. Lin |
| collection | DOAJ |
| description | Summary: Although flaviviruses co-opt the function of the host endoplasmic reticulum (ER) membrane protein complex (EMC) during infection, a mechanistic explanation for this observation remains unclear. Here, we show that the EMC promotes biogenesis of dengue virus (DENV) and Zika virus (ZIKV) non-structural multi-pass transmembrane proteins NS4A and NS4B, which are necessary for viral replication. The EMC binds to NS4B and colocalizes with the DENV replication organelle. Mapping analysis reveals that the two N-terminal marginally hydrophobic domains of NS4B confer EMC dependency. Furthermore, altering the hydrophobicity of these two marginally hydrophobic domains relieves NS4B’s EMC dependency. We demonstrate that NS4B biogenesis, but not its stability, is reduced in EMC-depleted cells. Our data suggest that the EMC acts as a multi-pass transmembrane chaperone required for expression of at least two virally encoded proteins essential for flavivirus infection and point to a shared vulnerability during the viral life cycle that could be exploited for antiviral therapy. : Multiple genetic screens have identified the ER membrane protein complex (EMC) as essential for infection by dengue and Zika flaviviruses. Lin et al. demonstrate that efficient biogenesis of the viral non-structural proteins NS4A and NS4B requires the EMC. Keywords: flavivirus, dengue virus, Zika virus, endoplasmic reticulum, ER membrane protein complex |
| first_indexed | 2024-12-22T15:49:52Z |
| format | Article |
| id | doaj.art-9febe1d429c84cf6855fe93b9a37b6de |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T15:49:52Z |
| publishDate | 2019-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-9febe1d429c84cf6855fe93b9a37b6de2022-12-21T18:20:55ZengElsevierCell Reports2211-12472019-05-0127616661674.e4The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support InfectionDavid L. Lin0Takamasa Inoue1Yu-Jie Chen2Aaron Chang3Billy Tsai4Andrew W. Tai5Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Infectious Pathogen Research Section, Central Research Laboratory, Research and Development Division, Japan Blood Products Organization, Kobe 650-0047, JapanDepartment of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Corresponding authorDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA; Corresponding authorSummary: Although flaviviruses co-opt the function of the host endoplasmic reticulum (ER) membrane protein complex (EMC) during infection, a mechanistic explanation for this observation remains unclear. Here, we show that the EMC promotes biogenesis of dengue virus (DENV) and Zika virus (ZIKV) non-structural multi-pass transmembrane proteins NS4A and NS4B, which are necessary for viral replication. The EMC binds to NS4B and colocalizes with the DENV replication organelle. Mapping analysis reveals that the two N-terminal marginally hydrophobic domains of NS4B confer EMC dependency. Furthermore, altering the hydrophobicity of these two marginally hydrophobic domains relieves NS4B’s EMC dependency. We demonstrate that NS4B biogenesis, but not its stability, is reduced in EMC-depleted cells. Our data suggest that the EMC acts as a multi-pass transmembrane chaperone required for expression of at least two virally encoded proteins essential for flavivirus infection and point to a shared vulnerability during the viral life cycle that could be exploited for antiviral therapy. : Multiple genetic screens have identified the ER membrane protein complex (EMC) as essential for infection by dengue and Zika flaviviruses. Lin et al. demonstrate that efficient biogenesis of the viral non-structural proteins NS4A and NS4B requires the EMC. Keywords: flavivirus, dengue virus, Zika virus, endoplasmic reticulum, ER membrane protein complexhttp://www.sciencedirect.com/science/article/pii/S2211124719305248 |
| spellingShingle | David L. Lin Takamasa Inoue Yu-Jie Chen Aaron Chang Billy Tsai Andrew W. Tai The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection Cell Reports |
| title | The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection |
| title_full | The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection |
| title_fullStr | The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection |
| title_full_unstemmed | The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection |
| title_short | The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection |
| title_sort | er membrane protein complex promotes biogenesis of dengue and zika virus non structural multi pass transmembrane proteins to support infection |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719305248 |
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