Binding of guide piRNA triggers methylation of the unstructured N-terminal region of Aub leading to assembly of the piRNA amplification complex

Xiawei Huang, Hongmiao Hu, Alexandre Webster, Fan Zou, Jiamu Du, Dinshaw J. Patel, Ravi Sachidanandam, Katalin Fejes Toth, Alexei A. Aravin () and Sisi Li ()
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Xiawei Huang: Pasadena California Institute of Technology
Hongmiao Hu: National Key Laboratory of Plant Molecular Genetics and Shanghai Center for Plant Stress Biology, Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences
Alexandre Webster: Pasadena California Institute of Technology
Fan Zou: Southern University of Science and Technology of China
Jiamu Du: Southern University of Science and Technology of China
Dinshaw J. Patel: Structural Biology Program, Memorial Sloan Kettering Cancer Center
Ravi Sachidanandam: Icahn School of Medicine at Mount Sinai
Katalin Fejes Toth: Pasadena California Institute of Technology
Alexei A. Aravin: Pasadena California Institute of Technology
Sisi Li: International Cancer Center, Shenzhen University Health Science Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract PIWI proteins use guide piRNAs to repress selfish genomic elements, protecting the genomic integrity of gametes and ensuring the fertility of animal species. Efficient transposon repression depends on amplification of piRNA guides in the ping-pong cycle, which in Drosophila entails tight cooperation between two PIWI proteins, Aub and Ago3. Here we show that post-translational modification, symmetric dimethylarginine (sDMA), of Aub is essential for piRNA biogenesis, transposon silencing and fertility. Methylation is triggered by loading of a piRNA guide into Aub, which exposes its unstructured N-terminal region to the PRMT5 methylosome complex. Thus, sDMA modification is a signal that Aub is loaded with piRNA guide. Amplification of piRNA in the ping-pong cycle requires assembly of a tertiary complex scaffolded by Krimper, which simultaneously binds the N-terminal regions of Aub and Ago3. To promote generation of new piRNA, Krimper uses its two Tudor domains to bind Aub and Ago3 in opposite modification and piRNA-loading states. Our results reveal that post-translational modifications in unstructured regions of PIWI proteins and their binding by Tudor domains that are capable of discriminating between modification states is essential for piRNA biogenesis and silencing.

Date: 2021
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DOI: 10.1038/s41467-021-24351-x

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