PRRC2 proteins regulate translation initiation by promoting leaky scanning

Teleman, Aurelio A.; Bohlen, Jonathan; Roiuk, Mykola

doi:10.1101/2022.11.11.516176

Cited by 3 publications

(4 citation statements)

References 56 publications

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“…These secondary or compensatory effects could result from the primary changes in TE of PRRC2B-bound mRNAs or the altered cell cycle progression upon PRRC2B knockdown (Figure 4) since translation varies dramatically in different phases of cell cycle (46). The PRRC2 proteins have been repeatedly linked with mRNA binding and posttranscriptional regulation (21)(22)(23)(47)(48)(49)(50). A recent study suggests that PRRC2 proteins facilitate leaky scanning of upstream open reading frames (uORF) (47).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…The PRRC2 proteins have been repeatedly linked with mRNA binding and posttranscriptional regulation (21–23,47–50). A recent study suggests that PRRC2 proteins facilitate leaky scanning of upstream open reading frames (uORF) (47). However, our results showed both mRNAs with and without uORFs are bound and regulated by PRRC2B, suggesting that the effect of PRRC2B is not limited to uORFs but determined by the presence of GA- and CU-rich binding sites.…”

Section: Discussionmentioning

confidence: 99%

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RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression

Jiang

Hedaya

Khor

et al. 2022

Preprint

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Accumulating evidence suggests that posttranscriptional control of gene expression, including RNA splicing, transport, modification, translation, and degradation, primarily relies on RNA binding proteins (RBPs). However, the functions of many RBPs remain understudied. Here, we characterized the function of a novel RBP, Proline-Rich Coiled-coil 2B (PRRC2B). Through photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and sequencing (PAR-CLIP-seq), we identified transcriptome-wide CU- or GA-rich PRRC2B binding sites around the translation initiation codon on a specific cohort of mRNAs in HEK293T cells. These mRNAs, including oncogenes and cell cycle regulators such asCCND2(cyclin D2), exhibited decreased translation upon PRRC2B knockdown as revealed by polysome-associated RNA-seq, resulting in reduced G1/S phase transition and cell proliferation. Antisense oligonucleotides blocking PRRC2B interactions withCCND2mRNA decreased its translation, thus inhibiting G1/S transition and cell proliferation. Mechanistically, PRRC2B interactome analysis revealed RNA-independent interactions with eukaryotic translation initiation factors 3 (eIF3) and 4G2 (eIF4G2). The interaction with translation initiation factors is essential for PRRC2B function since the eIF3/eIF4G2-interacting defective mutant, unlike wild-type PRRC2B, failed to rescue the translation deficiency or cell proliferation inhibition caused by PRRC2B knockdown. Altogether, our findings reveal that PRRC2B is essential for efficient translation of specific proteins required for cell cycle progression and cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression

Jiang

Hedaya

Khor

et al. 2022

Preprint

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“…A recent preprint showed that the eIF4G2-interacting proteins PRRC2A, PRRC2B, and PRRC2C also promote leaky scanning on certain, but not all, mRNAs ( Bohlen et al 2022 ). Strikingly, subsets of mRNAs that require eIF4G2 or PRRC2A-C for their translation at least partially overlap ( Bohlen et al 2022 ; Smirnova et al 2022 ). Future research will show how these proteins cooperate in facilitating leaky scanning.…”

Section: Proposed Mechanisms Of Eif4g2 Operation In Translation Initi...mentioning

confidence: 99%

Specific mechanisms of translation initiation in higher eukaryotes: the eIF4G2 story

Shestakova

Smirnova

Shatsky

et al. 2022

RNA

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The eukaryotic initiation factor 4G2 (eIF4G2, DAP5, Nat1, p97) was discovered in 1997. Over the past two decades, dozens of papers have presented contradictory data on eIF4G2 function. Since its identification, eIF4G2 has been assumed to participate in noncanonical translation initiation mechanisms, but recent results indicate that it can be involved in scanning as well. In particular, eIF4G2 provides leaky scanning through some upstream open reading frames (uORFs), which are typical for long 5’ UTRs of mRNAs from higher eukaryotes. It is likely the protein can also help the ribosome overcome other impediments during scanning of the 5’ UTRs of animal mRNAs. This may explain the need for eIF4G2 in higher eukaryotes, as many mRNAs that encode regulatory proteins have rather long and highly structured 5’ UTRs. Additionally, they often bind to various proteins, which also hamper the movement of scanning ribosomes. This review discusses the suggested mechanisms of eIF4G2 action, denotes obscure or inconsistent results, and proposes ways to uncover other fundamental mechanisms in which this important protein factor may be involved in higher eukaryotes.

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Loss-of-function of RNA-binding protein PRRC2B causes translational defects and congenital cardiovascular malformation

Das,

Khor,

Jiang

et al. 2024

Preprint

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Alternative splicing generates variant forms of proteins for a given gene and accounts for functional redundancy or diversification. A novel RNA-binding protein, Pro-rich Coiled-coil Containing Protein 2B (PRRC2B), has been reported by multiple laboratories to mediate uORF-dependent and independent regulation of translation initiation required for cell cycle progression and proliferation. We identified two alternative spliced isoforms in human and mouse hearts and HEK293T cells, full-length (FL) and exon 16-excluded isoform ∆E16. A congenital heart disease-associated human mutation-mimicry knock-in of the equivalent variant in the mouse genome leads to the depletion of the full-length Prrc2b mRNA but not the alternative spliced truncated form ∆E16, does not cause any apparent structural or functional disorders. In contrast, global genetic inactivation of the PRRC2B gene in the mouse genome, nullifying both mRNA isoforms, caused patent ductus arteriosus (PDA) and neonatal lethality in mice. Bulk and single nucleus transcriptome profiling analyses of embryonic mouse hearts demonstrated a significant overall downregulation of multiple smooth muscle-specific genes in Prrc2b mutant mice resulting from reduced smooth muscle cell number. Integrated analysis of proteomic changes in Prrc2b null mouse embryonic hearts and polysome-seq and RNA-seq multi-omics analysis in human HEK293T cells uncover conserved PRRC2B-regulated target mRNAs that encode essential factors required for cardiac and vascular development. Our findings reveal the connection between alternative splicing regulation of PRRC2B, PRRC2B-mediated translational control, and congenital cardiovascular development and disorder. This study may shed light on the significance of PRRC2B in human cardiovascular disease diagnosis and treatment.

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PRRC2 proteins regulate translation initiation by promoting leaky scanning

Cited by 3 publications

References 56 publications

RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression

RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression

Specific mechanisms of translation initiation in higher eukaryotes: the eIF4G2 story

Loss-of-function of RNA-binding protein PRRC2B causes translational defects and congenital cardiovascular malformation

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