5-methylcytosine modiﬁcation by Plasmodium NSUN2 stabilizes mRNA and mediates the development of gametocytes

PNAS, 2022 · DOI: https://doi.org/10.1073/pnas.2110713119 · Published: February 24, 2022

Simple Explanation

This study investigates the role of 5-methylcytosine (m5C), a modification in messenger RNA (mRNA), in the development of malaria parasites. The researchers found that m5C is more abundant in the sexual stages (gametocytes) of both rodent and human malaria parasites. They identified a specific enzyme, NSUN2, in Plasmodium parasites that acts as a major writer of m5C modifications on mRNA. Disrupting this enzyme in rodent malaria parasites led to reduced m5C levels and impaired gametocyte production. The study suggests that NSUN2-mediated m5C modifications play a critical role in stabilizing mRNA and promoting sexual differentiation in malaria parasites, potentially offering new targets for interrupting malaria transmission.

Study Duration

Not specified

Participants

Mice infected with Plasmodium yoelii, human erythrocytes infected with Plasmodium falciparum

Evidence Level

Molecular study

Key Findings

1
m5C mRNA methylation is strikingly enhanced in the transcriptomes of gametocytes in both Plasmodium yoelii and Plasmodium falciparum.
2
Plasmodium ortholog of NSUN2 is a major mRNA m5C methyltransferase in malaria parasites, and its knockout leads to marked reductions of m5C modification in gametocytogenesis-associated transcripts.
3
Disruption of Pynsun2 in P. yoelii and Pfnsun2 in P. falciparum resulted in dramatically reduced gametocyte production, which was rescued by restoration of Pynsun2 expression.

Research Summary

The study characterizes the landscape of m5C mRNA modifications in Plasmodium parasites, revealing higher levels in gametocytes. It identifies NSUN2 as a major mRNA m5C methyltransferase. Knockout of Pynsun2 impairs gametocyte production, which can be rescued by restoration of Pynsun2 expression, demonstrating the importance of NSUN2-mediated m5C modifications in mRNA transcript stability and sexual differentiation. The findings suggest that m5C modifications can stabilize mRNA transcripts and increase half-life, and they may also influence the export of the transcripts for translation in the cytoplasm.

Practical Implications

Drug target identification

NSUN2 could be a potential drug target for malaria transmission blocking strategies.

Understanding gametocytogenesis

m5C-mediated processes offer new insights into male and female gametocytogenesis and progression to mature ookinetes.

Further research

Further investigation of epitranscriptomic modifications may yield molecular pathways that might be exploited to interrupt malaria transmission.

Study Limitations

1
The exact mechanisms of m5C-mediated mRNA trafﬁcking in Plasmodium need further study.
2
Phenotypes associated with Plasmodium NSUN1, as well as NSUN3 and NSUN4, require further investigation.
3
The identification of an m5C eraser in eukaryotes is still lacking.

Your Feedback

Was this summary helpful?

Back to Immunology