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Metabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development

ABSTRACT: The blood-feeding behavior of Anopheles females delivers essential nutrients for egg development and drives parasite transmission between humans. Plasmodium growth is adapted to the vector reproductive cycle, but how changes in the reproductive cycle impact parasite development remains unclear. Here, we show that the bloodmeal-induced miR-276-5p fine-tunes the expression of branched-chain amino acid transferase to terminate the reproductive cycle. Silencing of miR-276 prolongs high rates of amino acid (AA) catabolism and increases female fertility, suggesting that timely termination of AA catabolism restricts mosquito investment into reproduction. Prolongation of AA catabolism in P. falciparum-infected females also compromises the development of the transmissible sporozoite forms. Our results suggest that Plasmodium sporogony exploits the surplus mosquito resources available after reproductive investment and demonstrate the crucial role of the mosquito AA metabolism in within-vector parasite proliferation and malaria transmission.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Gas Chromatography MS - positive, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS1282 | MetaboLights | 2021-11-03

REPOSITORIES: MetaboLights

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Metabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development.

Lampe Lena L Jentzsch Marius M Kierszniowska Sylwia S Levashina Elena A EA

Nature communications 20191210 1

The blood-feeding behavior of Anopheles females delivers essential nutrients for egg development and drives parasite transmission between humans. Plasmodium growth is adapted to the vector reproductive cycle, but how changes in the reproductive cycle impact parasite development remains unclear. Here, we show that the bloodmeal-induced miR-276-5p fine-tunes the expression of branched-chain amino acid transferase to terminate the reproductive cycle. Silencing of miR-276 prolongs high rates of amin ...[more]

PMID: 31822677

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Project description:The transmission of the malaria parasite between mosquitoes and mammals requires translational repression to ensure that only the proper proteins are expressed at the right time, while still allowing the parasite to prepare the mRNAs it will need for the next developmental stage. With relatively few known specific transcription factors (ApiAP2 family) that may specifically initiate gene transcription, Plasmodium parasites also regulate the stability and turnover of transcripts to provide more comprehensive gene regulation. The CAF1/CCR4/NOT complex has been shown in model organisms to be important for not only mRNA degradation, but also translational control through its deadenylases CAF1 and CCR4. However, few proteins that impose translational repression in Plasmodium sexual stages are known, and those that are characterized primarily affect female gametocytes. Therefore, we have characterized two deadenylases and have uncovered their roles in transmission. We have identified and characterized CCR4-1, which we show plays a role in activating male gametocytes, stabilizing transcripts in gametocytes, and regulating host-to-vector transmission. We find that when ccr4-1 is genetically deleted, there is a loss in the coordination of male gametocyte activation and a reduction in the ability of the parasite to productively infect the mosquito, which is independent of its effect upon male activation. Comparative RNA-seq shows that the deletion of ccr4-1 affects many transcripts that are translationally repressed in females, are related to male gamete function, and/or are important for early mosquito stage development. In contrast, we found that genetic deletion of the major deadenylase Caf1 is lethal. However, we observed that expression of only the N-terminal Caf1 domain is permissive, yet prevents proper complex assembly and phenocopies the ccr4-1 deletion. We therefore conclude that the general and transmission-specialized deadenylases of the CAF1/CCR4/NOT complex play critical and intertwined roles in parasite growth and transmission.

			Action	DRS
	01_GC.cdf	Other
	02_GC.cdf	Other
	03_GC.cdf	Other
	04_GC.cdf	Other
	05_GC.cdf	Other