PIWI Slicing and EXD1 Drive Biogenesis of Nuclear piRNAs from Cytosolic Targets of the Mouse piRNA Pathway

Mol Cell. 2016 Jan 7;61(1):138-52. doi: 10.1016/j.molcel.2015.11.009. Epub 2015 Dec 6.


PIWI-interacting RNAs (piRNAs) guide PIWI proteins to suppress transposons in the cytoplasm and nucleus of animal germ cells, but how silencing in the two compartments is coordinated is not known. Here we demonstrate that endonucleolytic slicing of a transcript by the cytosolic mouse PIWI protein MILI acts as a trigger to initiate its further 5'→3' processing into non-overlapping fragments. These fragments accumulate as new piRNAs within both cytosolic MILI and the nuclear MIWI2. We also identify Exonuclease domain-containing 1 (EXD1) as a partner of the MIWI2 piRNA biogenesis factor TDRD12. EXD1 homodimers are inactive as a nuclease but function as an RNA adaptor within a PET (PIWI-EXD1-Tdrd12) complex. Loss of Exd1 reduces sequences generated by MILI slicing, impacts biogenesis of MIWI2 piRNAs, and de-represses LINE1 retrotransposons. Thus, piRNA biogenesis triggered by PIWI slicing, and promoted by EXD1, ensures that the same guides instruct PIWI proteins in the nucleus and cytoplasm.

Keywords: Bombyx; Exd1; Inchworming; PIWI; Ping-pong; Slicer; Tdrd12; piRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Argonaute Proteins / chemistry
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism*
  • Carrier Proteins / metabolism
  • Cell Nucleus / enzymology*
  • Cytosol / enzymology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Exonucleases / chemistry
  • Exonucleases / genetics
  • Exonucleases / metabolism*
  • Female
  • Gene Expression Regulation
  • Male
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Protein Interaction Domains and Motifs
  • RNA Interference
  • RNA Processing, Post-Transcriptional*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*


  • Argonaute Proteins
  • Carrier Proteins
  • Drosophila Proteins
  • EXD1 protein, mouse
  • Multiprotein Complexes
  • PIWIL4 protein, mouse
  • Piwil1 protein, mouse
  • Piwil2 protein, mouse
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • piwi protein, Drosophila
  • tudor domain-containing protein 12, mouse
  • Exonucleases