# The role of XPO1 in nuclear export of RNA

> **NIH NIH R35** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $383,750

## Abstract

Project Summary
The focus of research in the Taylor laboratory is on nuclear export in eukaryotic cells, which we study by
perturbing the normal function of the main exporter of proteins, XPO1 or Exportin-1. We use molecular biology,
genomics, proteomics, and mouse modeling to determine the mechanisms of XPO1-mediated nuclear export
function and the role of XPO1 in disease pathogenesis. We also study how XPO1 interacts with other proteins
and molecules such as ribonucleic acid (RNA). In the next five years, the goal of the lab is to define the role of
XPO1 in the nuclear export of RNA. The laboratory is currently pursuing the following projects. Defining the
molecular effects of wildtype and mutant XPO1 on gene expression, splicing, and translation. Given the known
role of XPO1 in the export of small nuclear RNA (snRNA) and ribosomal RNA (rRNA) via the binding of RNA
binding proteins, we hypothesize that alterations in XPO1 may impact RNA splicing and/or mRNA translation.
We have generated several genetically engineered models to allow endogenous expression of the XPO1
E571K or R749Q mutation, including conditional knockin mice. We have demonstrated through a variety of
proteomic, biochemical, structural, and molecular studies that XPO1 E571K affects recognition of its cargo’s
nuclear export signal (NES) and results specifically in altered export of of NFκB and NFAT transcription factor
proteins. The aim of my first project is to continue to study the extent of how the XPO1 E571K alters nuclear
export and to explore whether RNA export, and consequent mRNA splicing and translation, is affected through
the mislocalization of RNA binding proteins. We have recently discovered another mutation, XPO1 R749Q, that
affects nuclear export by increasing the export of proteins out of the nucleus. We plan to study which proteins
this affects and how this affects cell growth, cell cycle and other homeostatic processes. We are also modeling
overexpression of XPO1 and will compare how this overactive mutant compares to overexpression in relation
to protein and RNA export. Drugs that selectively inhibit XPO1 will allow us to isolate the effects of XPO1-
dependent export. Furthermore, our preliminary data show that cells with abnormal splicing due to SF3B1
mutations undergo apoptosis upon exposure to XPO1 inhibitors. We will also investigate the effects of XPO1
inhibition in mutant Sf3b1 expressing cells using genetically engineered cell lines and an Sf3b1 knockin mouse
model. We hypothesis that XPO1 inhibition perturbs RNA export and affects gene expression and mRNA
splicing given the known role of XPO1 to export small nuclear RNA via RNA-binding proteins. This work will
serve as foundational data for future grant submissions investigating the biology of XPO1 and its role in
nuclear export of RNA. The overarching goal of this research is aligned with the NIGMS’ mission to
support new basic discovery science that can eventually culminate in new medical therapies. ...

## Key facts

- **NIH application ID:** 10899544
- **Project number:** 5R35GM151109-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Justin Taylor
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899544

## Citation

> US National Institutes of Health, RePORTER application 10899544, The role of XPO1 in nuclear export of RNA (5R35GM151109-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899544. Licensed CC0.

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