What is PfSortilin and what does it do?

PfSortilin is a protein found within the malaria parasite, *Plasmodium falciparum*. It functions as a guide, directing other proteins to their correct locations within the parasite's cells, specifically from the Golgi apparatus to the rhoptries. This role is crucial for the parasite's survival.

What are rhoptries and why are they important for the malaria parasite?

Rhoptries are specialized secretory organelles within the *Plasmodium* parasite that are essential for invading red blood cells. They are part of the apical complex and contain proteins necessary for the parasite to enter and establish itself within the host cell. Without properly functioning rhoptries, the parasite cannot effectively infect new cells.

What is RAMA and what is its role in the malaria parasite?

RAMA, or rhoptry-associated membrane antigen, is a protein that resides in the rhoptries and is critical for their function. It interacts with PfSortilin, which helps to transport RAMA and potentially other proteins to the rhoptries. Its GPI-anchored characteristic was previously thought to guide other rhoptry proteins.

Why is the interaction between PfSortilin and RAMA important?

The interaction between PfSortilin and RAMA is significant because it is essential for protein trafficking within the parasite. PfSortilin escorts RAMA from the Golgi apparatus to the rhoptries. Disrupting this interaction could prevent the proper formation and function of the rhoptries, thereby inhibiting the parasite's ability to invade red blood cells.

Illustration of PfSortilin proteins escorting RAMA proteins within a malaria parasite cell.

Unlocking Malaria's Secrets: How Proteins Navigate the Parasite's Cell

Q: How could this discovery potentially lead to new treatments for malaria?

This research identifies PfSortilin as a potential target for new antimalarial drugs. By disrupting PfSortilin's function or its interaction with RAMA, it may be possible to interfere with the formation of the rhoptries and prevent the parasite from infecting red blood cells. This approach could offer a new strategy for combating malaria, especially in light of increasing drug resistance. Further research is needed to identify the drug candidates.

Nico Varela in Science & Nature September 2025 • 4 min read.

"New research sheds light on the critical role of a protein called PfSortilin in transporting essential components within the malaria parasite, offering potential targets for future drug development."

Malaria continues to pose a significant global health challenge, particularly in tropical and subtropical regions. The disease, caused by Plasmodium parasites, claimed over 430,000 lives in 2015 alone, with Plasmodium falciparum being responsible for the most severe cases. The rise of drug-resistant strains and the lack of a fully effective vaccine underscore the urgent need for innovative intervention strategies.

The life cycle of Plasmodium parasites involves invading host cells, a process that relies on a complex interplay of organelles. Among these, rhoptries – specialized secretory organelles – play a crucial role in invading red blood cells. Understanding how these organelles are formed and how proteins are trafficked to them is essential for identifying potential vulnerabilities in the parasite.

Recent research has focused on the mechanisms behind rhoptry biogenesis, with a particular emphasis on the role of protein trafficking. One key player in this process is a protein called PfSortilin, a homologue of the transmembrane protein sortilin-VPS10. This article explores the groundbreaking findings regarding PfSortilin's function as an escort for the trafficking of rhoptry-associated membrane antigen (RAMA), a critical protein for rhoptry function.

Decoding PfSortilin's Role: The Protein Traffic Controller

Illustration of PfSortilin proteins escorting RAMA proteins within a malaria parasite cell.

Scientists have long been intrigued by how proteins are targeted to specific organelles within Plasmodium parasites. Previous research suggested that RAMA, a glycosylphosphatidylinositol (GPI)-anchored protein, might act as a guide for other rhoptry proteins. However, the mechanism by which this complex interacts with the cell's trafficking machinery remained unclear.

The recent study provides compelling evidence that PfSortilin, a protein with a conserved structure found in various organisms, interacts with RAMA and plays a crucial role in protein trafficking. Sortilins are known to act as escorts, directing proteins to their correct destinations within the cell. In the case of Plasmodium falciparum, PfSortilin appears to be responsible for transporting proteins from the Golgi apparatus to the rhoptries.

Here's a breakdown of the key findings:

PfSortilin Localization: PfSortilin was found to reside in the cis region of the Golgi apparatus, a key organelle involved in protein processing and trafficking.
RAMA Interaction: PfSortilin interacts with specific regions of RAMA, demonstrating a direct link between the two proteins.
Rhoptry Targeting: Regions of RAMA that interact with PfSortilin are sufficient to target a fluorescent reporter to the rhoptries, confirming the importance of this interaction for protein localization.

These findings suggest that PfSortilin acts as an escorter, ensuring that proteins destined for the rhoptries arrive at their correct location. This discovery provides valuable insight into the biogenesis of the apical complex, a critical structure for the malaria parasite's survival.

New Avenues for Malaria Intervention

The identification of PfSortilin as a key player in protein trafficking opens up new avenues for developing antimalarial drugs. By disrupting the interaction between PfSortilin and RAMA, or by interfering with PfSortilin's function, it may be possible to disrupt the formation of the rhoptries and prevent the parasite from invading red blood cells. Further research is needed to fully elucidate the mechanisms involved and to identify potential drug candidates that can target this pathway.