Alteration of miRNA activity via context-specific modifications of Argonaute proteins

• Ago proteins are subject to multiple types of post-translational modification.
• Ago modifications often occur following cell- or state-specific stimuli.
• Different Ago modifications can have selective or broad impacts on miRNA activity.

miRNAs are enclosed within Argonaute (Ago) proteins, the downstream effectors of small RNA-mediated gene silencing. Because miRNAs mediate extensive networks of post-transcriptional control, cells have evolved multiple strategies to control their activity with precision. A growing theme of recent years is how post-translational modifications of Ago proteins, such as prolyl hydroxylation, phosphorylation, ubiquitination, and poly-ADP-ribosylation, alter miRNA activity at global or specific levels. In this review, we discuss recent advances in Ago modifications in mammalian cells and emphasize how such alterations modulate small RNA function to coordinate appropriate downstream cellular responses. These findings provide a framework to understand how Ago protein modifications are linked to reorganization of post-transcriptional regulatory networks, enabling dynamic responses to diverse external stimuli and changing environmental conditions.