Eukaryotic translation initiation factor 2C (eIF2C) proteins (argonaute family) influence RNA interference (RNAi) as components of the RNA-inducible silencing complex (RISC) or microRNA (miRNA)-containing ribonucleoprotein particle (miRNP). Small RNAs, including small interfering RNAs (siRNAs) and miRNAs, can silence target genes through mechanisms that utilize RISC or miRNP particles. eIF2C1 (argonaute 1, AGO1, eIF2C, GERP95, Q99) and Dicer1 play a coordinated role in siRNA-mediated gene silencing. eIF2C2 (Slicer, argonaute 2, AGO2, Q10) is a RISC component that can concentrate in cytoplasmic processing bodies (P-bodies) and catalyze mRNA cleavage. Mammalian P-bodies contain mRNAs and have an association with miRNA-induced translational silencing and siRNA-induced mRNA degradation. Additional eIF2C proteins include eIF2C3 (argonaute 3, AGO3), eIF2C4 (argonaute 4, AGO4) and meIF2c5 (mouse argonaute 5).
Function:
Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include EIF2C2/AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISSLCmediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by EIF2C2/AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISSLCmediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also upregulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the 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 antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions.
Subunit:
Interacts with DICER1 through its Piwi domain and with TARBP2 during assembly of the RNA-induced silencing complex (RISC). Together, DICER1, EIF2C2/AGO2 and TARBP2 constitute the trimeric RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC). Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto EIF2C2/AGO2. EIF2C2/AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Note however that the term RISC has also been used to describe the trimeric RLC/miRLC. The formation of RISC complexes containing siRNAs rather than miRNAs appears to occur independently of DICER1. Interacts with EIF2C1/AGO1. Also interacts with DDB1, DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, EIF6, ELAVL, FXR1, GEMIN4, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, MOV10, PABPC1, PRMT5, P4HA1, P4HB, RBM4, SART3, TNRC6A, TNRC6B, UPF1 and YBX1. Interacts with the P-body components DCP1A and XRN1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with RBM4; the interaction is modulated under stress-induced conditions, occurs under both cell proliferation and differentiation conditions and in a RNA-and phosphorylation-independent manner. Interacts with LIMD1, WTIP and AJUBA. Interacts with TRIM71.
Subcellular Location:
Cytoplasm > P-body. Nucleus. Translational repression of mRNAs results in their recruitment to P-bodies. Translocation to the nucleus requires IMP8.
Post-translational modifications:
Hydroxylated. 4-hydroxylation appears to enhance protein stability but is not required for miRNA-binding or endonuclease activity.
Similarity:
Belongs to the argonaute family. Ago subfamily.
Contains 1 PAZ domain.
Contains 1 Piwi domain.
SWISS:
Q9UKV8
Gene ID:
27161
Database links:
Entrez Gene: 27161 Human
Entrez Gene: 239528 Mouse
Entrez Gene: 59117 Rat
Omim: 606229 Human
SwissProt: Q9UKV8 Human
SwissProt: Q8CJG0 Mouse
SwissProt: Q9QZ81 Rat
Unigene: 449415 Human
Unigene: 475937 Mouse
Unigene: 35512 Rat
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Sample:
Spleen (Mouse) Lysate at 40 ug
Primary: Anti-eIF2C2 (SL12450R) at 1/1000 dilution
Secondary: IRDye800CW Goat Anti-Rabbit IgG at 1/20000 dilution
Predicted band size: 97 kD
Observed band size: 97 kD
Sample:
Uterus (Mouse) Lysate at 40 ug
Primary: Anti-eIF2C2 (SL12450R) at 1/1000 dilution
Secondary: IRDye800CW Goat Anti-Rabbit IgG at 1/20000 dilution
Predicted band size: 97 kD
Observed band size: 97 kD
Paraformaldehyde-fixed, paraffin embedded (mouse kidney); Antigen retrieval by boiling in sodium citrate buffer (pH6.0) for 15min; Block endogenous peroxidase by 3% hydrogen peroxide for 20 minutes; Blocking buffer (normal goat serum) at 37°C for 30min; Antibody incubation with (AGO2) Polyclonal Antibody, Unconjugated (SL12450R) at 1:200 overnight at 4°C, followed by operating according to SP Kit(Rabbit) (sp-0023) instructionsand DAB staining.
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