# Genetic regulation and immunological function of ERAP2 haplotypes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $698,086

## Abstract

We propose to dissect the genetic control and immunological function of ERAP2, a gene previously shown to
play a role in antigen processing. Two haplotypes at the ERAP2 locus have been maintained by natural
selection in humans where the more frequent haplotype (Haplotype B) is associated with risk for Crohn's
disease, ankylosing spondylitis, preeclampsia and HIV susceptibility. Enigmatically, while Haplotype A encodes
a full-length enzyme that cleaves viral peptides for antigen presentation, Haplotype B encodes a transcript
efficiently degraded by nonsense-mediated decay. Why would natural selection have maintained a seemingly
loss-of-function version of the gene and by what mechanism would it cause disease? We found a possible
explanation by studying the antiviral response of monocyte-derived dendritic cells in 250 healthy individuals. In
response to in vitro stimulations, influenza infection induced the transcription of two unannotated short isoforms
from Haplotype B that are not observed in resting or interferon-beta stimulated cells. This observation,
combined with previous immunological results and evidence of natural selection, leads us to hypothesize that
the two ERAP2 haplotypes encode distinct gene products that play divergent roles in viral antigen processing
and presentation. In this proposal, we will apply state-of-the-art molecular and immunological tools to test this
hypothesis. In Aim 1, we will use functional genomic techniques (long-read RNA-seq, ribosomal footprinting
and proteomics) to characterize the transcriptional and translational properties of ERAP2 in response to a
spectrum of viral challenges. In Aim 2, we will map the cis-genetic control of ERAP2 using reporter assays and
CRISPR/Cas9-mediated genome editing. In Aim 3, we will measure how different ERAP2 isoforms affect
antigen presentation and T cell function. Our findings will shed new light on the regulation and function of the
ERAP2 haplotypes and contribute to the understanding of how genetic variants under natural selection could
cause autoimmune disease.

## Key facts

- **NIH application ID:** 9937630
- **Project number:** 5R01AI136972-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Chun Jimmie Ye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $698,086
- **Award type:** 5
- **Project period:** 2018-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937630

## Citation

> US National Institutes of Health, RePORTER application 9937630, Genetic regulation and immunological function of ERAP2 haplotypes (5R01AI136972-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9937630. Licensed CC0.

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