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The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection.

Cell reports | 2019

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.

Pubmed ID: 31067454 RIS Download

Research resources used in this publication

Antibodies used in this publication

Associated grants

  • Agency: NIAID NIH HHS, United States
    Id: T32 AI007528
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK097374
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI064296
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK034933
  • Agency: NIDDK NIH HHS, United States
    Id: T32 DK094775

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