eIF4G2 balances its own mRNA translation via a PCBP2-based feedback loop

Smirnova, Victoria V.; Shestakova, Ekaterina D.; Bikmetov, Dmitry; Chugunova, Anastasia; Osterman, Ilya А.; Serebryakova, Marina V.; Sergeeva, Olga V.; Zatsepin, Timofei S.; Shatsky, Ivan N.; Terenin, Ilya M.

doi:10.1261/rna.065623.118

Cited by 17 publications

(33 citation statements)

References 70 publications

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“…It has been demonstrated that PCBP2 facilitates the antiviral activity of IFNα against the Hepatitis C virus by stabilizing the mRNA of STAT1 and STAT2 in hepatocyte cell lines (28). Stabilization of mRNA molecules usually implies the binding of PCBP2 to the 3′-UTRs (28,41), but some studies have revealed that PCBP2 can also bind 5′-UTRs of mRNA molecules, inhibiting their translation (42).…”

Section: Discussionmentioning

confidence: 99%

The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA

González-Moro

Olazagoitia-Garmendia

Colli

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The vast majority of type 1 diabetes (T1D) genetic association signals lie in noncoding regions of the human genome. Many have been predicted to affect the expression and secondary structure of long noncoding RNAs (lncRNAs), but the contribution of these lncRNAs to the pathogenesis of T1D remains to be clarified. Here, we performed a complete functional characterization of a lncRNA that harbors a single nucleotide polymorphism (SNP) associated with T1D, namely, Lnc13. Human pancreatic islets harboring the T1D-associated SNP risk genotype in Lnc13 (rs917997*CC) showed higher STAT1 expression than islets harboring the heterozygous genotype (rs917997*CT). Up-regulation of Lnc13 in pancreatic β-cells increased activation of the proinflammatory STAT1 pathway, which correlated with increased production of chemokines in an allele-specific manner. In a mirror image, Lnc13 gene disruption in β-cells partially counteracts polyinosinic-polycytidylic acid (PIC)-induced STAT1 and proinflammatory chemokine expression. Furthermore, we observed that PIC, a viral mimetic, induces Lnc13translocation from the nucleus to the cytoplasm promoting the interaction of STAT1 mRNA with (poly[rC] binding protein 2) (PCBP2). Interestingly, Lnc13-PCBP2 interaction regulates the stability of the STAT1 mRNA, sustaining inflammation in β-cells in an allele-specific manner. Our results show that the T1D-associated Lnc13 may contribute to the pathogenesis of T1D by increasing pancreatic β-cell inflammation. These findings provide information on the molecular mechanisms by which disease-associated SNPs in lncRNAs influence disease pathogenesis and open the door to the development of diagnostic and therapeutic approaches based on lncRNA targeting.

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Section: Discussionmentioning

confidence: 99%

The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA

González-Moro

Olazagoitia-Garmendia

Colli

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…The human β-actin, CCNI, eIF4G2, murine Map3k3, Pcbp2, human TNFα, TP53 ( 31 ), APAF1 ( 34 ), ATF4, IFRD1, UCP2 ( 35 ), leaderless ( 36 ), rabbit β-globin, HIV1 ( 37 ), L1JK ( 38 ) reporter plasmids were described previously. The human AKT2, ARRDC4, ATF3, ATF5, BCL2, CDK1, CES2, eIF5, EPAS1, HERC1, hnRNPK (both variants), HSPA2, c-jun, PCBP1, PKR, PPFIA4, SMAD1, TGFβ1, TNRC6C, UHMK1 5′ UTRs were amplified from cDNA obtained from 293T cells.…”

Section: Methodsmentioning

confidence: 99%

“…The majority of reports claim that the protein drives internal translation initiation ( 16 , 21–29 ), while a few others point to a specific cap-dependent translation initiation mechanism when the cap-recognizing factor eIF4E is dispensable ( 17 , 30 ). However, the protein has also been suggested to participate in conventional cap-dependent translation ( 19 , 31 ). Thus, it is still unclear whether the only role of eIF4G2 is to functionally replace eIF4G1 under specific conditions or whether it can also assist the latter.…”

Section: Introductionmentioning

confidence: 99%

Ribosomal leaky scanning through a translated uORF requires eIF4G2

Smirnova

Shestakova

Nogina

et al. 2022

Nucleic Acids Research

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eIF4G2 (DAP5 or Nat1) is a homologue of the canonical translation initiation factor eIF4G1 in higher eukaryotes but its function remains poorly understood. Unlike eIF4G1, eIF4G2 does not interact with the cap-binding protein eIF4E and is believed to drive translation under stress when eIF4E activity is impaired. Here, we show that eIF4G2 operates under normal conditions as well and promotes scanning downstream of the eIF4G1-mediated 40S recruitment and cap-proximal scanning. Specifically, eIF4G2 facilitates leaky scanning for a subset of mRNAs. Apparently, eIF4G2 replaces eIF4G1 during scanning of 5′ UTR and the necessity for eIF4G2 only arises when eIF4G1 dissociates from the scanning complex. In particular, this event can occur when the leaky scanning complexes interfere with initiating or elongating 80S ribosomes within a translated uORF. This mechanism is therefore crucial for higher eukaryotes which are known to have long 5′ UTRs with highly frequent uORFs. We suggest that uORFs are not the only obstacle on the way of scanning complexes towards the main start codon, because certain eIF4G2 mRNA targets lack uORF(s). Thus, higher eukaryotes possess two distinct scanning complexes: the principal one that binds mRNA and initiates scanning, and the accessory one that rescues scanning when the former fails.

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“…Herein, it was found that PCBP2 had a binding cite for miR‐490‐3p according to bioinformatical analysis, and DL reporter assay confirmed the interaction of miR‐490‐3p and PCBP2. As a member of the PCBP family, PCBP2 has the function of maintaining mRNA stability and regulating translation 36 . PCBP2 is involved in the regulation of signal molecule post‐transcription and translation via binding to the single‐stranded poly(C) motifs 37 .…”

Section: Discussionmentioning

confidence: 99%

Role of miR‐490‐3p in blocking bladder cancer growth through targeting the RNA‐binding protein PCBP2

Zhang

Song

Wang

et al. 2021

The Kaohsiung J of Med Scie

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MiR‐490‐3p is regarded as a tumor suppressor in many cancers, but whether miR‐490‐3p is involved in the development of bladder cancer remains unknown. BALB/c nude mice (male, 15–20 g) were used to investigate the role of MiR‐490‐3p in bladder cancer. The relationship between miR‐490‐3p and PCBP2 involved in bladder cancer regulation were determined. Cell viability, proliferation, and cell cycle were estimated by cell counting kit‐8 (CCK‐8) assay, 5‐bromo‐2′‐deoxyuridine (BrdU) detection, and flow cytometry analysis, respectively. In animal experiments, lentivirus was transfected into bladder cancer cells to overexpress miR‐490‐3p, which were then injected into mice and the change of tumor volume was assessed. Principal findings: The expression of MiR‐490‐3p was decreased in bladder cancer cells. Overexpression of miR‐490‐3p inhibited bladder cancer cell viability and proliferation. Moreover, overexpression of miR‐490‐3p caused cell cycle arrest in bladder cancer cells. The inhibitory effect of miR‐490‐3p on bladder cancer cells growth could be counteracted by enhancing PCBP2 expression. In vivo, bladder cancer growth in mice was blocked by miR‐490‐3p upregulation. MiR‐490‐3p suppressed bladder cancer growth and bladder cancer cell proliferation by down‐regulating PCBP2 expression.

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eIF4G2 balances its own mRNA translation via a PCBP2-based feedback loop

Cited by 17 publications

References 70 publications

The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA

The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA

Ribosomal leaky scanning through a translated uORF requires eIF4G2

Role of miR‐490‐3p in blocking bladder cancer growth through targeting the RNA‐binding protein PCBP2

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