# PTEX mechanism in malaria parasite effector protein export and host cell subversion

> **NIH NIH R01** · IOWA STATE UNIVERSITY · 2024 · $366,297

## 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 for deciphering fundamental parasite biology to provide novel
therapeutic strategies. This obligate intracellular parasite exports a battery of effector proteins out
of a vacuolar niche to drastically remodel its host cell, a process that depends on the Plasmodium
Translocon of EXported proteins (PTEX). PTEX is built on a vacuole nutrient pore formed by
EXP2 which is further functionalized by the adaptor PTEX150 and AAA+ chaperone HSP101 to
form the effector translocon. PTEX has emerged as a novel drug target owing to its essential role
in blood stage parasite survival and disease pathogenesis but it is unknown how translocon cargo
is identified or how the complex is assembled and regulated to perform its function. Recent results
suggest HSP101 identifies export-destine cargo in the parasite ER and then brings it to the
vacuole where assembly into the PTEX complex stimulates HSP101’s unfolding activity to drive
membrane translocation into the erythrocyte. Importantly, while a similar export process is
expected to occur in the initial liver infection that establishes the blood stage, only EXP2 and
PTEX150 are present in the intrahepatic vacuole but not HSP101. This implies that PTEX
components mediate protein export into both erythrocytes and hepatocytes but that mechanistic
distinctions have evolved to meet the demands of subverting these remarkably different host cells.
In support of this, we recently determined that EXP2 is critical to intrahepatic parasite
development, clearly showing for the first time that PTEX components are also functional in the
liver stage vacuole. We hypothesize that EXP2/PTEX150 constitutes a minimal effector
translocon for vertebrate host cell subversion that is further adapted by HSP101 to meet
the unique demands on protein export to remodel the erythrocyte. This proposal will answer
key questions about the PTEX export mechanism to determine the basis for host cell subversion
and provide new targets to combat this devastating pathogen. Aim 1 will determine the basis for
PTEX cargo selection in the blood stage by dissecting the ER-localized function of HSP101 along
with the role of a newly discovered HSP101-interacting ER protein. Aim 2 will define features
required to form PTEX and identify the interaction that stimulates HSP101 unfolding activity in the
assembled translocon complex using a photoreactive unnatural amino acid crosslinking system.
Finally, Aim 3 will uncover the HSP101-independent function of EXP2/PTEX150 in the liver and
identify novel exported effectors that enable hepatocyte subversion to establish the blood stage.

## Key facts

- **NIH application ID:** 10872168
- **Project number:** 5R01HL170104-02
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Josh Ryan Beck
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $366,297
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872168

## Citation

> US National Institutes of Health, RePORTER application 10872168, PTEX mechanism in malaria parasite effector protein export and host cell subversion (5R01HL170104-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10872168. Licensed CC0.

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