Partners in Silencing: Decoding the Mammalian Argonaute Interactome
Abstract
1. Introduction
2. The Argonaute Family of Proteins
2.1. Sumoylation of AGO
2.2. Phosphorylation of AGO
2.3. Ubiquitination of AGO
2.4. Acetylation of AGO
2.5. Poly-ADP-Ribosylation of AGO
2.6. Hydroxylation of AGO
miRISC Interactors | Interacting AGO | Functionality | Remarks | References |
---|---|---|---|---|
Sumoylation of AGO | ||||
RANBP2 | AGO 1-2 | Associates with E2 enzyme UBC9 and induces the sumoylation of AGO1/2 | - | [62] |
PIAS3 | AGO2 | E3 SUMO protein ligase that catalyzes the final steps of the sumoylation of K402-AGO2 | - | [64] |
Phosphorylation of AGO | ||||
CSNK1A1 | AGO 1-3 | Phosphorylation of the EI region of AGO proteins | - | [66,69] |
ANKRD52 | AGO 2 | Dephosphorylation of EI region of AGO2 | - | [66] |
TBK1 | AGO2 | Phosphorylates S417-AGO2 | Promotes the formation of pS417-AGO2-miR-21-RISC in NSCLC | [70] |
EGFR | AGO2 | Phosphorylates Y103-AGO2 | During hypoxia, decreased pY103-AGO2 and DICER interaction | [76] |
C-Src | AGO2 | Phosphorylates Y393/529/749-AGO2 | pY393 sustains interaction with DICER | [77] |
PTP1B | AGO2 | De-phosphorylates Y393-AGO2 | - | [78] |
E-cadherins | AGO2 | Mediates pAGO2 by ER-kinase signaling | - | [79] |
Ubiquitination of AGO | ||||
STUB1 | AGO 1-4 | Adds polyubiquitin chains to K48-AGO | - | [81] |
CRL-ZSWIM8 | AGO2 | Presumably ubiquitinates K493-AGO2 | ZSWIM8 mediates TDMD in a tailing and trimming independent manner | [85] |
LUBAC system | AGO2 | Couples Met1 linear poly-ubiquitin chain to K820-AGO2 | This mechanism occurs mainly during hypoxia | [87] |
OTULIN | AGO2 | De-linear Deubiquitinating enzyme of AGO2 | - | [87] |
Acetylation of AGO | ||||
CBP | AGO2 | Acetylates K720/K493/K355-AGO2 | The acetylation of K493/K720-AGO2 promotes the biogenesis of pre-miR-19b | [88] |
HDAC7 | AGO2 | De-acetylate AGO2 | - | [88] |
Poly ADP-Ribosylation | ||||
PARP | AGO 1-4 | Catalyzes Poly (ADP-ribose) polymerization of AGO proteins | Mainly present in stress granules | [89] |
3. Unexpected Functions of miRISC
3.1. Interactors of AGO Proteins That Modulate miRISC Activities
3.2. Splicing-Associated Factors
3.3. mRNA Translation Associated Factors
3.4. RISC Associated Proteins That Control Localization and miRNA Sorting
3.5. Miscellaneous Factors Regulating RISC Activities
4. Conclusions
Funding
Conflicts of Interest
References
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miRISC Interactors | AGO Binding | Functionality | Remarks | Refs. |
---|---|---|---|---|
DICER | AGO 1-4 | Pre-miRNA processing | - | [5,13,24,34,35] |
GW182 family (TNRC6A/B/C) | AGO 1-4 | Scaffold protein to recruit other factors of miRISC | - | [36,37] |
CCR4-NOT complex | AGO 1-4 via GW182 proteins | Involved in de-adenylation mediated miRISC mechanisms | - | [36,38] |
PAN2-PAN3 | AGO2 | Involved in a 2-stage de-adenylation process with CCR4-NOT complex | - | [27,39] |
PABP | AGO 1-4 via GW182 proteins | Involved in de-adenylation mediated miRISC mechanisms | - | [26,40] |
CAF1 | AGO 1-2 | Additional de-adenylase in context-dependent miRISC functionality | - | [26] |
PARN | AGO2 | Involved in miR-125b-AGO2 RISC repression of TP53 | Also involved in pre-miR-451 biogenesis pathway along with AGO2 | [29,41] |
DDX6 | AGO 2 | Functions as an activator of decapping enzymes DCP1/DCP2 | - | [30] |
DHX9 | AGO 2-3 | RNA helicase that functions in RISC assembly and miRNA loading | - | [42] |
DCP1/DCP2 | AGO 1-2 | Supports de-capping of target mRNAs to promote 5′ to 3′ nucleolytic activity | - | [31] |
XRN1 | Not directly | Mediates 5′ to 3′ mRNA decay and is recruited by EDC4 | Implicated in miRISC-mediated silencing | [43] |
TRBP | AGO2 via DICER | Promotes dsRNA binding to RLC | - | [15,44] |
PACT | AGO2 via DICER | Promotes dsRNA binding to RLC | - | [15,17] |
Hsc70 | AGO2 | Involved in ATP- dependent conformation change in AGO2 to enable miRNA loading | - | [18] |
Hsp90 | AGO2 | - | [18] | |
p23 | AGO2 | Part of the Hsc70/Hsp90 chaperone complex for miRISC loading | - | [19] |
miRISC Interactors | AGO Binding | Core/ Auxiliary Factors | Functionality | Remarks | References |
---|---|---|---|---|---|
FKBP4 | AGO2 | Auxiliary | Promotes ATP-dependent loading of miRNAs in RISC | - | [19] |
CSDE1 | AGO2 | Auxiliary | Binds pre-miR-451, AGO2 and PARN to enhance trimming of the hairpin | - | [51,93] |
Tryptophan (Amino Acid) | AGO 1-4 | Auxiliary | Enhances nuclease activity of AGO2 | - | [96] |
DDX21 | AGO2 | Auxiliary | Increases nuclear AGO2 levels | - | [97] |
SF3B3 complex | AGO3 | Auxiliary | Promotes Nisch splicing to increase IL-13 expression in T cells | - | [98] |
STAU2 | AGO2 | Auxiliary | STAU2 regulates global translation by miRISC | - | [99] |
FMRP | AGO2 | Auxiliary | FMRP-mediates translational control by AGO2-miRISC | [117,118] | |
MOV10 | AGO 1-3 | Auxiliary | MOV10 relieves complex secondary structures in 3′-UTRs to augment AGO-miRISC binding to MRE | - | [102,119] |
APOBEC3G | Indirect activity | - | Binds MOV10 to inhibit AGO2-miRISC interaction to mRNAs | - | [120] |
CAV-1 | AGO2 | Auxiliary | Sorting of AGO2 RISC into EVs | Observed in breast cancer | [103] |
Lamin A | Indirect activity | - | Inhibits RISC activity | - | [106] |
PI(4,5)P2 | AGO2 | - | AGO RNPs condensation on ER membranes | Controls proteasomal degradation of nascent peptides | [107] |
LASP1 | AGO2 | Auxiliary | Enhances translational repression of Let-7a targets | This interaction is a CXCR4-dependent mechanism | [108] |
LIMD1 | AGO2 | Auxiliary | A pS387-AGO2-dependent mechanism decreasing translation of mRNA targets | Upon LIMD1 depletion in cells, AGO3-WTIP becomes the dominant miRISC | [114] |
TP53 | AGO2 | Auxiliary | Facilitates sorting of Let-7 miRNAs into AGO2-miRISC | TP53 may alter the conformation of AGO2 to promote loading of Let-7 miRNAs into RISC | [116] |
FKBP4 | AGO2 | Auxiliary | Enhances ATP-dependent loading of miRNAs into miRISC | [19] |
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Narasimhan, S.; Erkeland, S.J. Partners in Silencing: Decoding the Mammalian Argonaute Interactome. Non-Coding RNA 2025, 11, 62. https://doi.org/10.3390/ncrna11040062
Narasimhan S, Erkeland SJ. Partners in Silencing: Decoding the Mammalian Argonaute Interactome. Non-Coding RNA. 2025; 11(4):62. https://doi.org/10.3390/ncrna11040062
Chicago/Turabian StyleNarasimhan, Srinaath, and Stefan J. Erkeland. 2025. "Partners in Silencing: Decoding the Mammalian Argonaute Interactome" Non-Coding RNA 11, no. 4: 62. https://doi.org/10.3390/ncrna11040062
APA StyleNarasimhan, S., & Erkeland, S. J. (2025). Partners in Silencing: Decoding the Mammalian Argonaute Interactome. Non-Coding RNA, 11(4), 62. https://doi.org/10.3390/ncrna11040062