Protease-mediated processing of Argonaute proteins controls small RNA association.

Small RNA pathways defend the germlines of animals against selfish genetic elements, yet pathway activities need to be contained to prevent silencing of self genes. Here, we reveal a proteolytic mechanism that controls endogenous small interfering (22G) RNA activity in the Caenorhabditis elegans germline to protect genome integrity and maintain fertility. We find that DPF-3, a P-granule-localized N-terminal dipeptidase orthologous to mammalian dipeptidyl peptidase (DPP) 8/9, processes the unusually proline-rich N termini of WAGO-1 and WAGO-3 Argonaute (Ago) proteins. Without DPF-3 activity, these WAGO proteins lose their proper complement of 22G RNAs. Desilencing of repeat-containing and transposon-derived transcripts, DNA damage, and acute sterility ensue. These phenotypes are recapitulated when WAGO-1 and WAGO-3 are rendered resistant to DPF-3-mediated processing, identifying them as critical substrates of DPF-3. We conclude that N-terminal processing of Ago proteins regulates their activity and promotes silencing of selfish genetic elements by ensuring Ago association with appropriate small RNAs. [Display omitted] • DPF-3, a DPPIV family protease, protects C. elegans fertility • Loss of DPF-3 alters cellular endo-siRNA profiles and desilences transposons • DPF-3-mediated processing of WAGO-1/-3 Argonaute proteins promotes siRNA sorting • A combination of processing-refractive WAGO-1 and WAGO-3 phenocopies DPF-3 loss Gudipati et al. reveal that certain Argonaute proteins in C. elegans are processed at their N termini by a dipeptidase of the DPPIV family. This protein maturation event protects animal fertility by promoting sorting of the right type of small RNA, targeting transposable elements, to these Argonaute proteins. [ABSTRACT FROM AUTHOR]