MIWI2

MIWI2, also known as Piwi-like protein 4 (PIWIL4) in mice, is a member of the Piwi clade of the Argonaute protein family. It is one of the mammalian Piwi proteins involved in the piRNA pathway, which uses small non-coding RNAs to regulate transposable elements and maintain genome integrity in the germ line. In mice, MIWI2 expression is highest in developing male germ cells during fetal stages.

MIWI2 participates in the biogenesis and function of PIWI-interacting RNAs (piRNAs). It binds a subset of piRNAs that are derived largely from transposon sequences and forms a piRNA-induced silencing complex (piRISC). Through this complex, MIWI2 is involved in directing de novo DNA methylation and transcriptional silencing of transposable elements, contributing to epigenetic reprogramming and genome stability during spermatogenesis. The activity of MIWI2 is coordinated with other Piwi proteins and Tudor domain-containing factors, and its localization can change during germ cell development, reflecting stages of piRNA production and silencing.

Genetic disruption of MIWI2 in mice leads to failure to establish proper DNA methylation of transposons, derepression of transposable elements, and defects in spermatogenesis, often resulting in male infertility. This underscores the essential role of MIWI2 in protecting the germ line from genomic instability.

In humans, the orthologous gene PIWIL4 encodes a HIWI2-like protein that participates in the mammalian piRNA pathway, with conserved functions in transposon silencing and germline development, though species-specific details of expression and regulation may differ. MIWI2 is therefore a key component of the conserved piRNA machinery that preserves genome integrity in mammalian males.