How does the royal family of Tudor rule the PIWI-interacting RNA pathway?

Abstract

PIWI (P-element-induced wimpy testis) proteins are a subset of the Argonaute proteins and are expressed predominantly in the germlines of a variety of organisms, including Drosophila and mammals. PIWI proteins associate specifically with PIWI-interacting RNAs (piRNAs), small RNAs that are also expressed predominantly in germlines, and silence transposable DNA elements and other genes showing complementarities to the sequences of associated piRNAs. This mechanism helps to maintain the integrity of the genome and the development of gametes. PIWI proteins have been shown recently to contain symmetrical dimethyl arginines (sDMAs), and this modification is mediated by the methyltransferase PRMT5 (also known as Dart5 or Capsuleen). It was then demonstrated that multiple members of the Tudor (Tud) family of proteins, which are necessary for gametogenesis in both flies and mice, associate with PIWI proteins specifically through sDMAs in various but particular combinations. Although Tud domains in Tud family members are known to be sDMA-binding modules, involvement of the Tudor family at the molecular level in the piRNA pathway has only recently come into focus.

Figure 1.

Arginine methylation status of PIWI proteins. Mouse PIWI (A; MILI and MIWI) and fly PIWI (B; Aub and AGO3) N-terminal sequences are shown with putative sDMA motifs (red). Identified methylation sites (dimethylation [dMe] or monomethylation [mMe]) are shown above the relevant arginine, with the residue numbers below. Underlined sequences indicate the synthetic peptides that have been used in studies for pull-down assays. The MILI peptide corresponds to L69–T80 and R74 is an sDMA (Reuter et al. 2009). The MIWI peptide corresponds to M1–T18, and R4, R6, R8, R10, R12, and R14 are sDMAs (Kirino et al. 2010). The Aub peptides correspond to M1–N20 (Kirino et al. 2010) and M1–N25 (Nishida et al. 2009), and R11, R13, and R15 are sDMAs. The AGO3 peptides correspond to M1–K25 and T58–H82, and R4 in the M1–K25 peptide and R68 and R70 in the T58–H82 peptide are sDMAs (Nishida et al. 2009).