Malaria remains a complicated global health problem that is on the precipice of a resurgence in areas where it has long since subsided if climate change continues its “heated” rise. Understanding the molecular mechanisms that allow this pervasive parasite to traverse multiple hosts could hold the key to disease elimination, or, at the very least, keeping outbreaks under control. Now, investigators at Penn State University (PSU) have uncovered that malaria parasites have not one, but two, specialized proteins that protect its messenger RNAs (mRNAs) until the parasite takes up residence in a new mosquito or a human host. Findings from the new study were published recently in mSphere in an article entitled “Nuclear, Cytosolic, and Surface-Localized Poly(A)-Binding Proteins of Plasmodium yoelii.”
In the new study the, the PSU researchers describe the two proteins—known as poly(A)-binding proteins (PABPs)—and reveal an additional role that one PABP may play to facilitate RNA-based interactions between the parasite, its mosquito vector, and its human host.
“Understanding the malaria parasite and how it interacts with its host may provide insights that could help prevent the spread of this often-fatal disease,” explained senior study investigator Scott Lindner, Ph.D., assistant professor of biochemistry and molecular biology at Penn State. “The malaria parasite has a complex life cycle that includes phases in the mosquito vector, the human liver, and human blood. Moreover, the parasite has no idea when it's going to be transmitted from a mosquito to a human host and back, so it always needs to be ready to be transmitted. It prepares for this by making and packaging up the mRNAs that it will eventually need for making proteins inside its new host or a new mosquito.”
During this process—dubbed translational repression—special proteins bind to mRNAs and prevent them from being translated into protein. One PABP binds to the mRNA's poly(A) tail. This helps to form a complex of proteins and RNA that is silenced but poised for action after the parasite is transmitted to the host. Most single-celled organisms have one type of PABP, while multicellular organisms have two. However, in this study, the investigators characterize two types of PABPs in the single-celled Plasmodium parasite, both of which contribute to translational regulation.
“We knew from our lab's previous work that Plasmodium had a type of PABP that functions outside of the nucleus of the cell,” noted lead study author Allen Minns, a research technologist in Dr. Linder’s laboratory. “This protein binds and protects the poly(A) tail at one end of an mRNA strand. In this study, we used biochemical approaches to further characterize this protein and found that it also has a specialized job receiving mRNAs. It forms chains without the presence of RNA, which potentially allows large assemblies of the protein to quickly protect the entire length of the poly(A) tail.”
The PSU team was also able to identify and characterize a second type of PABP that functions inside the nucleus of the parasite during the blood stages of its life cycle. In multicellular organisms, this second PABP usually performs a quality control check before mRNA exits the nucleus, confirming that the mRNA is constructed properly. These quality control proteins then pass on the mRNA strand to other proteins outside of the nucleus, which direct the mRNA to be translated or to be packaged for later use through translational repression.
Interestingly, in addition to a key role in translational regulation inside of the cell, the researchers also discovered that the nonnuclear PABP might play a surprising role outside of the cell.
“When the parasite takes the form of a sporozoite in the mosquito, we actually don't see the vast majority of the nonnuclear PABP inside the cell where we expected it to be—where it would interact with mRNAs produced by the parasite,” remarked Dr. Lindner. “Instead, the protein accumulates at the surface of the sporozoite and is shed when the parasite moves. We don't see this happening in other life stages of the parasite, and this is now the third RNA-binding protein found to be on the surface of the sporozoite. The parasite is putting these RNA-binding proteins out there on its surface for a reason. The new and exciting question is why.”
The researchers speculate that the PABP on the sporozoite surface allows the parasite to interact with RNA from sources outside of the parasite and could thus provide an opportunity for the parasite to interact with the mosquito or the host through their RNA.
“This study suggests that the parasite's interaction with outside RNA is probably much more pervasive than we thought it was,” Dr. Lindner concluded. “It is possible that this kind of interaction could eventually provide a new target for intervention strategies, but the first step is understanding why the malaria parasite has these PABPs on the sporozoite surface.”