Ago3

Ago3, short for Argonaute 3, is a member of the Argonaute family of proteins that mediate gene silencing by small RNAs. It is found in a range of metazoans, including humans and mice. Argonautes bind small RNA guides and direct either cleavage of target RNAs or repression of translation, depending on context and the presence of catalytic activity in the PIWI domain.

Ago3 contains the characteristic PAZ and PIWI domains common to Argonautes. In many species it associates with small RNAs, notably piRNAs in germ cells and siRNAs in somatic and experimental settings. In mammals, Ago3 is primarily associated with the piRNA pathway in the germline, where it participates in the ping-pong amplification cycle that maintains piRNA populations and helps silence transposable elements.

Biological role: In mice, Ago3 is expressed in the testes and engages with Piwi-family proteins to repress transposons and support normal spermatogenesis. Genetic disruption of Ago3 in mice results in defects in germ cell development and reduced fertility, highlighting its role in germline integrity.

Although Ago2 is typically the main slicer among Argonautes, Ago3 and other non-slicer Argonautes usually show limited or no endonuclease activity. Instead, Ago3 functions through RNA-guided silencing complexes to regulate gene expression and transposon control, partly by guiding the production and stabilization of piRNAs and by interacting with other components of the silencing machinery.

In humans, AGO3 is one of four Argonaute proteins (AGO1–AGO4). It contributes to small RNA pathways and gene regulation, though its precise biological contributions diverge from those of AGO2 and may be context-dependent, particularly in the germline or in specialized silencing pathways.