The human body manages gene expression through various systems. One such system involves the Argonaute family of proteins, including AGO3. This protein’s primary role is in RNA interference, a process that helps control the flow of genetic information within cells.
The Argonaute Family and RNA Interference
Argonaute proteins are central to RNA interference (RNAi), a natural biological process that cells employ to regulate gene expression and defend against foreign genetic material. This mechanism involves small RNA molecules, such as microRNAs (miRNAs) and small interfering RNAs (siRNAs), which guide Argonaute proteins to specific target RNAs. These small RNAs are short, non-coding RNA fragments.
When an Argonaute protein binds to a small RNA, it forms a complex that can then identify and interact with messenger RNA (mRNA) molecules that have complementary sequences. This interaction can lead to the repression of translation, preventing the mRNA from being converted into a protein. RNA interference thus acts as a cellular defense system, capable of silencing genes or neutralizing viral genetic material.
How AGO3 Works
AGO3 binds to short RNA molecules, such as microRNAs and small interfering RNAs. Once bound, it can repress the translation of messenger RNAs that possess complementary sequences. This protein is also thought to help stabilize small RNA derivatives that come from RNA polymerase III-transcribed RNA.
A distinct feature of human AGO3 is its catalytic tetrad, Asp–Glu–Asp–His, which it shares with AGO2, another Argonaute protein. While historically considered to have limited RNA cleavage activity, recent discoveries reveal that human AGO3 can become an effective “slicer,” an enzyme capable of cleaving RNA. This enhanced activity occurs when AGO3 is activated by specific 14-nucleotide guide RNAs, referred to as cleavage-inducing tyRNAs, which can boost target cleavage by up to approximately 82-fold. For instance, a 14-nucleotide variant of miR-20a increased AGO3’s slicing activity about 30-fold more than its 23-nucleotide full-length form. The catalytic center of AGO3 is necessary for this RNA cleavage, as demonstrated by experiments using a catalytically inactive mutant.
AGO3 primarily localizes to the cytoplasm of cells. Beyond humans, AGO3 exhibits diverse roles in other organisms. In Arabidopsis, AGO3 preferentially binds to 24-nucleotide small RNAs, differing from AGO2 which binds shorter ones. It accumulates in specific plant tissues, such as aerial vascular terminations and chalazal seed integuments, potentially mediating post-transcriptional gene silencing by inhibiting translation.
In Drosophila, AGO3 is found in perinuclear “nuage” granules within germline cells. It participates in a process called piRNA biogenesis, where it binds sense piRNAs that typically have an adenosine at position 10 and are complementary to antisense piRNAs bound by other Argonaute proteins like Aub or Piwi. Notably, AGO3’s recruitment to these nuage granules in Drosophila is independent of its piRNA cargo, instead relying on an interaction with a protein called Krimper.
AGO3 and Human Health
AGO3’s proper functioning is relevant to human health, as its associations have been observed in specific medical conditions. For instance, AGO3 is linked to diseases such as Optic Nerve Hypoplasia, Bilateral, a condition affecting the development of the optic nerve, and Primary Hyperoxaluria, a disorder involving excessive oxalate production. These connections underscore AGO3’s involvement in various biological processes that, when disrupted, can lead to health challenges.
AGO3 is also part of broader biological pathways that regulate cellular activities. It is associated with processes like Transcriptional Regulation by MECP2, which involves controlling gene expression through a DNA-binding protein. Additionally, AGO3 plays a part in Cell junction organization, important for how cells connect and communicate within tissues. These associations highlight AGO3’s wide-ranging influence in maintaining cellular structure and function.