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

被引:21
|
作者
Liu, Meng [1 ,2 ]
Guo, Gangqiang [1 ,2 ,3 ]
Qian, Pengge [4 ]
Mu, Jianbing [5 ]
Lu, Binbin [3 ]
He, Xiaoqin [6 ]
Fan, Yanting [3 ]
Shang, Xiaomin [3 ]
Yang, Guang [1 ,2 ]
Shen, Shijun [1 ,2 ]
Liu, Wenju [1 ,2 ]
Wang, Liping [1 ,2 ]
Gu, Liang [1 ,2 ]
Mu, Quankai [7 ]
Yu, Xinyu [7 ]
Zhao, Yuemeng [3 ,8 ]
Culleton, Richard [9 ,10 ]
Cao, Jun [6 ]
Jiang, Lubin [8 ]
Wellems, Thomas E. [5 ]
Yuan, Jing [4 ]
Jiang, Cizhong [1 ,2 ]
Zhang, Qingfeng [3 ]
机构
[1] Tongji Univ, Orthopaed Dept, Sch Life Sci & Technol,Minist Educ,Tongji Hosp, Key Lab Spine & Spinal Cord Injury Repair & Regen, Shanghai 200092, Peoples R China
[2] Tongji Univ, Sch Life Sci & Technol, Shanghai Key Lab Signaling & Dis Res, Shanghai 200092, Peoples R China
[3] Tongji Univ, Tongji Hosp, Clin Ctr Brain & Spinal Cord Res,Sch Med,Minist E, Key Lab Spine & Spinal Cord Injury Repair & Regen, Shanghai 200092, Peoples R China
[4] Xiamen Univ, Innovat Ctr Cell Signaling Network, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China
[5] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA
[6] Jiangsu Inst Parasit Dis, Natl Hlth Commiss, Jiangsu Prov Key Lab Parasite & Vector Control Te, Key Lab Parasit Dis Control & Prevent, Wuxi 214064, Jiangsu, Peoples R China
[7] Nagasaki Univ, Inst Trop Med, Dept Immunogenet, Nagasaki 8528523, Japan
[8] Chinese Acad Sci, Univ Chinese Acad Sci, Inst Pasteur Shanghai, Unit Human Parasite Mol & Cell Biol,Key Lab Mol V, Shanghai 200031, Peoples R China
[9] Ehime Univ, Proteo Sci Ctr, Div Mol Parasitol, Matsuyama, Ehime 7908577, Japan
[10] Nagasaki Univ, Inst Trop Med, Dept Protozool, Nagasaki 8528521, Japan
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
RNA methyltransferase; gametocytogenesis; epitranscriptomic  modifications; RNA bisulfite sequencing; gene knockout; SEXUAL DEVELOPMENT; GENOME SEQUENCE; METHYLATION; METHYLTRANSFERASE; TRANSCRIPTOME; COMMITMENT; OOKINETE; READERS; WRITERS; M(5)C;
D O I
10.1073/pnas.2110713119
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
5-methylcytosine (m5C) is an important epitranscriptomic modification involved in messenger RNA (mRNA) stability and translation efficiency in various biological processes. However, it remains unclear if m5C modification contributes to the dynamic regulation of the transcriptome during the developmental cycles of Plasmodium parasites. Here, we characterize the landscape of m5C mRNA modifications at single nucleotide resolution in the asexual replication stages and gametocyte sexual stages of rodent (Plasmodium yoelii) and human (Plasmodium falciparum) malaria parasites. While different representations of m5C-modified mRNAs are associated with the different stages, the abundance of the m5C marker is strikingly enhanced in the transcriptomes of gametocytes. Our results show that m5C modifications confer stability to the Plasmodium transcripts and that a Plasmodium ortholog of NSUN2 is a major mRNA m5C methyltransferase in malaria parasites. Upon knockout of P. yoelii nsun2 (pynsun2), marked reductions of m5C modification were observed in a panel of gametocytogenesisassociated transcripts. These reductions correlated with impaired gametocyte production in the knockout rodent malaria parasites. Restoration of the nsun2 gene in the knockout parasites rescued the gametocyte production phenotype as well as m5C modification of the gametocytogenesis-associated transcripts. Together with the mRNA m5C profiles for two species of Plasmodium, our findings demonstrate a major role for NSUN2-mediated m5C modifications in mRNA transcript stability and sexual differentiation in malaria parasites.
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页数:11
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