AGO2 gene

The AGO2 gene (AGO2 stands for: Argonaute RISC Catalytic Component 2) is a protein-coding gene located on chromosome 8q24.3. Several transcript variants encoding different isoforms have been found for this gene. An important paralog of this gene is AGO1.

The AGO2 gene encodes a member of the Argonaute family of proteins that play a role in RNA interference. The encoded protein is highly basic and contains a PAZ domain and a PIWI domain. It possibly interacts with Dicer1 and plays a role in short-interfering RNA-mediated gene silencing.

The encoded protein AGO2 is required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The "minimal RISC" appears to contain AGO2 bound to a short guide RNA such as a microRNA (miRNA) or a short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing.

Binding of RISC to a perfectly complementary mRNA generally leads to silencing by endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of RISC to a partially complementary mRNA leads to silencing by inhibition of translation, independent of endonuclease activity (Lessel D et al. 2020). AGO2 can inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing recruitment of the translation initiation factor eIF4-E. AGO2 can also inhibit translation initiation by interacting with EIF6, which in turn binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. Inhibition of translation initiation leads to accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation can subsequently take place. In some cases, RISC-mediated translational repression is also observed in miRNAs that perfectly match the 3'-untranslated region (3'-UTR).

AGO2 can also upregulate translation of certain mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of TNF (TNF-alpha) mRNA and upregulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigen RNAs or agRNAs direct the transcriptional repression of complementary promoter regions.

AGO2 associates with a viral miRNA-like small RNA, CoV2-miR-O7a, in Sars-CoV-2 infection and can repress mRNAs such as BATF2 to bypass the IFN response.

Diseases associated with AGO2 include:

• Lessel-Kreienkamp syndrome
• and
• non-specific syndromic mental retardation.

1. Chendrimada TP et al. (2007) MicroRNA silencing through RISC recruitment of eIF6. Nature. 447:823-828.
2. Gregersen LH et al. (2014) MOV10 Is a 5' to 3' RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3' UTRs. Mol Cell 54:573-585.
3. Lessel D et al. (2020) Germline AGO2 mutations impair RNA interference and human neurological development. Nat Commun 11:5797.