# Identifying a Critical Gatekeeper for DNA Virus Restriction

> **NIH NIH F31** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $33,790

## Abstract

ABSTRACT
 APOBEC3B (A3B) is an innate immune enzyme capable of introducing mutations in viral genomes and
has been implicated in the restriction of several viruses. In addition, A3B is unique as the only human DNA
deaminase family member that is constitutively nuclear. Recent studies have shown that -herpesviruses, such
as Epstein-Barr virus (EBV), have evolved potent mechanisms for A3B neutralization and re-localization. The
ribonucleotide reductase of EBV, BORF2, is capable of binding and relocalizing A3B from the nuclear
compartment to cytoplasmic aggregates. Therefore, nuclear localization has been inferred to be essential for
innate antiviral function. Regarding A3B subcellular localization, we have previously shown that A3B nuclear
localization requires the presence of three residues within the N-terminal half of the protein and that nuclear
localization is not a conserved feature of A3B across non-human primates, despite a need for antiviral function
in the nuclear compartment. For instance, although human and several non-human primate A3B enzymes are
predominantly nuclear, rhesus macaque and other Old World monkey A3B enzymes are clearly cytoplasmic. A
series of human/rhesus macaque chimeras and mutants combined to map localization determinants to the N-
terminal half of the protein with residues 15, 19, and 24 proving critical. Despite advances in our knowledge of
A3B, the mechanism of nuclear localization and the broad role of subcellular localization in virus restriction
activities remain uncharacterized. Taken together, we hypothesize that A3B uses a non-canonical mechanism
of nuclear import and that nuclear localization is a key feature of A3B’s role as a restriction factor. This hypothesis
will be tested through two complementary Specific Aims. The first will identify the molecular mechanism of A3B
nuclear import through evolutionary and proteomics approaches, using the human/rhesus macaque chimeras
described above. The second will address whether nuclear localization is required for A3B-mediated antiviral
activities by testing A3B and select mutants against a panel of viruses in cell culture and in vivo. These studies
will elucidate the mechanism of A3B nuclear import and the role of subcellular localization in DNA virus
restriction, thus enhancing our understanding of these important host-pathogen interactions.

## Key facts

- **NIH application ID:** 10826729
- **Project number:** 1F31AI181573-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Ashley A Auerbach
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $33,790
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-05-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10826729

## Citation

> US National Institutes of Health, RePORTER application 10826729, Identifying a Critical Gatekeeper for DNA Virus Restriction (1F31AI181573-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10826729. Licensed CC0.

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