# UIS2 function in establishing transport mechanisms at the malaria parasite-host cell interface

> **NIH NIH R21** · IOWA STATE UNIVERSITY · 2024 · $186,642

## Abstract

Project Summary
Malaria disease remains a serious public health problem. Progress in Malaria control has slowed
in recent years while resistance to frontline antimalarials is emerging in the most afflicted regions,
underscoring a pressing need to decipher the fundamental biology of the parasite to provide novel
therapeutic options. During the pathogenic blood stage, malaria parasites develop within a
protective vacuole inside host erythrocytes. Export of effector proteins out of the vacuole remodels
the host cell to create a niche for replication while transport of nutrients across this barrier fuels
rapid parasite growth. Both of these processes depend on a vacuole membrane pore formed by
the parasite protein EXP2, which allows small molecule exchange between the host cytosol and
vacuole and is also assembled into the PTEX complex to mediate translocation of effector
proteins into the host cell. While these mechanisms are critical to parasite survival and disease
pathogenesis, it is unknown how EXP2/PTEX function is specifically established in the vacuole
membrane. We recently identified an interaction between EXP2/PTEX and UIS2, a secreted
parasite protein that also localizes to the vacuole. Preliminary observations suggest UIS2 is an
integral protein of the vacuolar membrane and conditional knockdown of UIS2 in Plasmodium
falciparum revealed an essential function in protein export. We hypothesize that UIS2 is
required to establish EXP2 function in the PVM, critically enabling both protein export and
nutrient uptake. UIS2 contains a purple acid phosphatase domain but is unlikely to be
catalytically active as it appears to be missing several key metal coordinating residues. Aim 1 will
study the membrane association and topology of UIS2 and evaluate the catalytic activity of the
phosphatase domain in vitro and its importance to UIS2 function in vivo. Aim 2 will investigate the
function of UIS2 in transport across the vacuolar membrane by determining its precise impact on
EXP2 and formation of the nutrient pore. These studies will define the role of UIS2 in PVM
transport processes critical to parasite survival and Malaria pathology. Intriguingly, UIS2 is broadly
conserved among vacuole-dwelling apicomplexans and the Toxoplasma ortholog of UIS2, known
as GRA44, is also critical to an analogous but mechanistically distinct protein export pathway.
Thus UIS2/GRA44 may represent a unifying feature of the vacuolar export machinery in these
diverse apicomplexans that could suggest novel, widely applicable control strategies for this
important group of pathogens.

## Key facts

- **NIH application ID:** 10738791
- **Project number:** 5R21AI173810-02
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Josh Ryan Beck
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $186,642
- **Award type:** 5
- **Project period:** 2022-11-10 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10738791

## Citation

> US National Institutes of Health, RePORTER application 10738791, UIS2 function in establishing transport mechanisms at the malaria parasite-host cell interface (5R21AI173810-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10738791. Licensed CC0.

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