# Defining the functional interface between the ER and flaviviruses

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $615,421

## Abstract

Flaviviruses are a genus of related positive-stranded enveloped RNA viruses that significantly
impact human health, including dengue (DENV), Zika (ZIKV). West Nile (WNV), Japanese
encephalitis (JEV), and yellow fever (YFV) viruses. The discovery of host factors critical for viral
infection reveals new aspects of cell biology, intricate virus-host relationships, and potential
targets for antiviral therapeutics. After entering cells and fusing in the acidified endosome, the
flavivirus RNA genome penetrates into the cytoplasm and is then translated into a polyprotein and
processed at the endoplasmic reticulum (ER). In addition to utilizing many functions of the ER for
protein production, flaviviruses extensively remodel ER membranes to create a niche for RNA-
dependent RNA replication. The ER also is the site for flavivirus assembly, which enables the
production and secretion of new infectious viruses. Thus, the ER serves as a central point for
orchestrating many of the essential steps in the flavivirus infection life cycle. Despite this, little is
known about the host factors and molecular mechanisms at the ER that are required for optimal
translation and processing of the viral proteins or for the assembly of the replication niche. We
recently have performed several genetic screens to identify important components in this process.
Our genome-wide RNAi screen with WNV in insect cells validated 18 genes associated with ER
biology that promote infection. Our CRISPR/Cas9 gene-editing screen in human cells with WNV
also identified 12 ER-associated genes. These screens converged on ER-resident proteins as
being critical for WNV infection and included genes associated with ER-translocation and signal
peptide processing, ER-associated degradation (ERAD), protein glycosylation, protein folding and
lipid metabolism. Indeed, infection of WNV, ZIKV, JEV, DENV, and YFV all required specific
subunit components of the host signal peptidase complex (SPCS) for processing of the viral
polyprotein, the production of viral glycoproteins and thus generation of nascent virions. The
objective of this proposal is to define the molecular mechanisms by which flaviviruses use specific
ER-associated host proteins to promote viral translation, polyprotein processing, RNA replication,
and/or assembly. Aim 1 will define the mechanism by which the ER translocon promotes
polyprotein translation and processing while Aim 2 will dissect the role of ER-associated decay
(ERAD) in promoting flavivirus replication. Our long-term goal is to determine the mechanisms by
which flaviviruses exploit the ER for their replication, as this will reveal both fundamental aspects
of virology as well as new avenues for antiviral therapeutics.

## Key facts

- **NIH application ID:** 9928366
- **Project number:** 5R01AI140539-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sara Cherry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $615,421
- **Award type:** 5
- **Project period:** 2018-06-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928366

## Citation

> US National Institutes of Health, RePORTER application 9928366, Defining the functional interface between the ER and flaviviruses (5R01AI140539-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928366. Licensed CC0.

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