SUMOylation of Argonaute-2 regulates RNA interference activity

Abstract

Post-translational modification of substrate proteins by small ubiquitin-like modifier (SUMO) regulates a vast array of cellular processes. SUMOylation occurs through three sequential enzymatic steps termed E1, E2 and E3. Substrate selection can be determined through interactions between the target protein and the SUMO E2 conjugating enzyme Ubc9 and specificity can be enhanced by substrate interactions with E3 ligase enzymes. We used the putative substrate recognition (PINIT) domain from the SUMO E3 PIAS3 as bait to identify potential SUMO substrates. One protein identified was Argonaute-2 (Ago2), which mediates RNA-induced gene silencing through binding small RNAs and promoting degradation of complimentary target mRNAs. We show that Ago2 can be SUMOylated in mammalian cells by both SUMO1 and SUMO2. SUMOylation occurs primarily at K402, and mutation of the SUMO consensus site surrounding this lysine reduces Ago2-mediated siRNA-induced silencing in a luciferase-based reporter assay. These results identify SUMOylation as a potential regulator of Ago2 activity and open new avenues for research into the mechanisms underlying the regulation of RNA-induced gene silencing.

Nup358 binds to AGO proteins through its SUMO ‐interacting motifs and promotes the association of target mRNA with miRISC

“…Previous studies have shown that human AGO2 gets SUMOylated at lysine 402 [77,78]. Consistent with this, we also found that the lysine residue 402, but not 266 or 693, of human AGO2 is modified by SUMO (Appendix Fig S3A).…”

Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis

“…AGO2 acts as an efficient modulator in regulating miRNA processing, miRNA-guided gene silencing and other functions through various PTMs, including prolyl-4-hydroxylation [20, 21], phosphorylation [22–26], ubiquitination [27, 33], polyADP-ribosylation [28] and SUMOylation [34]. Our study for the first time identified that AGO2 was acetylated.…”

LncRNA profile study reveals four-lncRNA signature associated with the prognosis of patients with anaplastic gliomas

“…We further explored the interaction properties with proteins of the four lncRNAs using CLIPdb and starBase V2.0 (Table 3). AGO2 can play a role of RNA interference by encoding a member of argonaute family of proteins [27] and it predictively interacted with TPT1-AS1 and MIR155HG. It is reported that AGO2 can regulate tumor invasion, proliferation, apoptosis and cell cycle in glioma, cervical and prostate cancer [28–30].…”