# The Putative E3 Ubiquitin Ligase TEX1 Is Required for Nuclear Biology and Developmental Progression of Plasmodium berghei in the Liver

## TL;DR

The study shows that the protein TEX1 is essential for the development of malaria parasites in the liver and mosquito stages, making it a potential target for new treatments.

## Contribution

The novel contribution is the functional characterization of TEX1 as a critical E3 ubiquitin ligase in Plasmodium development.

## Key findings

- Disruption of TEX1 leads to severe defects in nuclear division and liver stage progression in Plasmodium berghei.
- C-terminal HA tagging of TEX1 reveals a discrete subnuclear localization pattern during liver stage development.
- TEX1 is a promising target for liver stage and transmission-blocking antimalarial interventions.

## Abstract

What are the main findings?
TEX1 knockout parasites display severe defects in nuclear division, organelle segregation, and developmental progression during mosquito and liver stages.C-terminal HA tagging preserves TEX1 function and reveals a strong, discrete subnuclear localization pattern during liver stage development.

TEX1 knockout parasites display severe defects in nuclear division, organelle segregation, and developmental progression during mosquito and liver stages.

C-terminal HA tagging preserves TEX1 function and reveals a strong, discrete subnuclear localization pattern during liver stage development.

What are the implications of the main findings?
TEX1 is a critical regulator of parasite nuclear biology and liver stage schizogony, and its precise localization supports a role in chromatin- or division-associated processes.Disruption of TEX1 effectively blocks the transition from liver to blood stage, highlighting TEX1 as a promising target for liver stage and transmission-blocking interventions.

TEX1 is a critical regulator of parasite nuclear biology and liver stage schizogony, and its precise localization supports a role in chromatin- or division-associated processes.

Disruption of TEX1 effectively blocks the transition from liver to blood stage, highlighting TEX1 as a promising target for liver stage and transmission-blocking interventions.

Malaria remains a major global health burden, and the emergence of resistance to blood stage antimalarials underscores the need for new interventions targeting earlier stages of the parasite’s life cycle. The pre-erythrocytic liver stage represents a critical bottleneck and an attractive target for chemotherapeutic and prophylactic interventions. In this study, we functionally characterized the putative E3 ubiquitin ligase Trophozoite Exported Protein 1 (TEX1; PBANKA_0102200) in Plasmodium berghei using gene knockout, tagging, and imaging approaches across the mosquito and liver stages. TEX1 knockout parasites (PbTEX1-KO) showed impaired development during mosquito-stage transitions, with significant reductions in ookinete formation, oocyst numbers, and sporozoites reaching the salivary glands. In hepatic stages, TEX1-KO parasites displayed reduced growth, abnormal nuclear division, and impaired liver stage maturation, ultimately leading to a dramatic decline in detached cell formation and blood stage infectivity. Endogenous C-terminal tagging of TEX1 with GFP and 3×HA revealed a discrete subnuclear localization pattern, indicating a critical role in DNA synthesis and/or mitotic regulation. Our findings reveal that TEX1 is required for nuclear replication and division and successful development in both the mosquito and liver stages of Plasmodium. Given its pivotal role and nuclear localization during hepatic schizogony, TEX1 represents a promising target for the development of liver stage antimalarial interventions.