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A University of California, Riverside-led team has made an advance in the basic understanding of Plasmodium falciparum, the parasite responsible for the deadliest form of human malaria, that could make novel, highly targeted anti-malarial therapies possible.

Led by Karine Le Roch, a professor of molecular, cell and systems biology, the team identified two key proteins inside the "apicoplast"—a unique, parasite-specific organelle found in P. falciparum—that control gene expression. These proteins belong to the RAP (RNA-binding domain Abundant in Apicomplexans) family of proteins. Far more numerous in parasites than in humans, RAP proteins play critical roles in regulating RNA molecules and translating them into proteins inside parasite organelles.

Using advanced genetic tools, the team created knockdown strains of P. falciparum to selectively deactivate the two RAP proteins, PfRAP03 and PfRAP08. The team found the loss of either protein led to parasite death, confirming their essential roles.

The researchers also discovered that PfRAP03 and PfRAP08 specifically bind to ribosomal RNA (rRNA) and transfer RNA (tRNA) molecules, respectively. These non-coding RNAs are fundamental to protein synthesis within the apicoplast.

"This is the first time anyone has shown how RAP proteins in the apicoplast directly interact with rRNA and tRNA," said Le Roch, who directs the UCR Center for Infectious Disease Vector Research. "We've now shown mechanistically how these proteins regulate translation in an organelle that's completely foreign to the human body."

Le Roch explained that humans have six RAP proteins, but parasites like Plasmodium have more than 20.

"This evolutionary expansion suggests that RAP proteins may perform parasite-specific functions, making them exciting drug targets," she said.

The study, in Cell Reports, builds on the team's previous research on RAP proteins in parasite mitochondria and represents the first detailed mechanistic analysis of their function in the apicoplast.

Unlike any structure found in human cells, the apicoplast is unique to apicomplexan parasites—a large group of single-celled organisms that includes Plasmodium, Toxoplasma gondii, and Babesia. This uniqueness makes it an ideal target for therapies that can eliminate the parasite without harming the human host.

"While the focus of our paper is malaria, the implications extend to other apicomplexan diseases like —dangerous especially to pregnant women—and babesiosis, a growing tick-borne threat in the United States," Le Roch said. "This work exposes vulnerabilities across an entire class of parasites, revealing the molecular machinery these parasites rely on. If we can take it apart, we can stop these diseases before they take hold."

Though no drugs currently target RAP proteins, Le Roch's lab is working toward solving the 3D structure of these RNA-protein complexes, a crucial step toward structure-guided drug design.

"Our research is a step toward future therapeutic strategies," Le Roch said. "By targeting essential, parasite-specific proteins that have no human counterparts, we can develop drugs that are both effective and have minimal side effects."

Le Roch was joined in the study by first author Thomas Hollin, Zeinab Chahine, Steven Abel, Todd Lenz, Jacques Prudhomme, Caitlyn Marie Ybanez, and Anahita S. Abbaszadeh of UCR; Charles Banks and Laurence Florens of the Stowers Institute for Medical Research, Kansas City, Missouri; and Charisse Flerida A. Pasaje and Jacquin C. Niles of the Massachusetts Institute of Technology, Cambridge, Massachusetts.