Protein Argonaute-2 and RNA-induced silencing complex components (AGO2/RISC)

Protein Argonaute-2 (AGO2) is the central catalytic component of the RNA-induced silencing complex (RISC), which plays a fundamental role in the RNA interference (RNAi) pathway. AGO2 is an endoribonuclease that uses a small RNA guide (siRNA or miRNA) to recognize and cleave complementary messenger RNA (mRNA) molecules, thereby preventing the translation of specific proteins (UniProt P98170). This mechanism is exploited by a growing class of therapeutic oligonucleotides, such as Patisiran and Inclisiran, which are designed to silence genes associated with diseases like hereditary transthyretin-mediated amyloidosis and hypercholesterolemia (PubMed: 30401519). Beyond its role in gene silencing, AGO2 is involved in microRNA-mediated translational repression and is often dysregulated in various cancers, where it can promote tumor progression (PubMed: 25231977). Therapeutic strategies targeting or utilizing the AGO2/RISC machinery must balance potent gene knockdown with the risk of off-target effects and the potential to saturate the cell's natural RNAi capacity (PubMed: 16729026). The complex is also essential for maintaining cellular homeostasis by regulating the stability and activity of endogenous microRNAs (PubMed: 21307310).

Other names

AGO2EIF2C2Eukaryotic translation initiation factor 2C 2PPDQ10RNA-induced silencing complexRISC

The RISC complex, powered by the catalytic activity of Argonaute-2, utilizes a guide RNA strand to identify and bind complementary mRNA sequences, leading to mRNA cleavage or translational inhibition.