The Ribosomal Protein Rpl22 Controls Ribosome Composition by Directly Repressing Expression of Its Own Paralog, Rpl22l1

O’Leary, Monique N.; Schreiber, Katherine H.; Zhang, Yong; Duc, Anne Cécile E; Rao, Shuyun; Hale, J. Scott; Academia, Emmeline C.; Shah, Shreya; Morton, John; Holstein, Carly A.; Martin, Dan; Kaeberlein, Matt; Ladiges, Warren; Fink, Pamela J.; MacKay, Vivian L.; Wiest, David L.; Kennedy, Brian K.

doi:10.1371/journal.pgen.1003708

Cited by 93 publications

(103 citation statements)

References 80 publications

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“…Our results indicate that, unlike other ribosomal proteins that have been shown to either activate p53 translation or act as Mdm2 antagonists under physiological conditions, Rpl22 directly suppresses p53 translation in a cell type-and developmental stage-specific manner, namely in cells undergoing V(D)J recombination. This finding agrees with previous reports that Rpl22-deficient mice exhibit no defects in global translation, but are defective specifically in regulation of p53 expression during pro-B cell and pre-T cell development (29,30,43). The data presented here strongly suggest that this regulation occurs through Miz-1, and that Miz-1 is a direct upstream regulator of the Rpl22 gene.…”

Section: Cd19supporting

confidence: 93%

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination

Rashkovan

Vadnais

Ross

et al. 2014

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

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To be effective, the adaptive immune response requires a large repertoire of antigen receptors, which are generated through V(D)J recombination in lymphoid precursors. These precursors must be protected from DNA damage-induced cell death, however, because V(D)J recombination generates double-strand breaks and may activate p53. Here we show that the BTB/POZ domain protein Miz-1 restricts p53-dependent induction of apoptosis in both pro-B and DN3a pre-T cells that actively rearrange antigen receptor genes. Miz-1 exerts this function by directly activating the gene for ribosomal protein L22 (Rpl22), which binds to p53 mRNA and negatively regulates its translation. This mechanism limits p53 expression levels and thus contains its apoptosis-inducing functions in lymphocytes, precisely at differentiation stages in which V(D)J recombination occurs.T he development of T lymphocytes starts with early thymic progenitors (ETPs) that first enter the thymus after transiting through the bloodstream from the bone marrow. These progenitor cells differentiate through four CD4 − CD8 − double-negative stages of development (DN1-4) before becoming first CD4 + CD8 + double-positive (DP) cells and then either CD4 + or CD8 + single positive T cells. The four DN subsets are differentiated based on their expression of the cell surface markers CD44 and CD25. Cells at the DN3 stage (CD44 − CD25 + ) are fully committed to the T cell lineage and require signaling through cytokine receptors and Notch1 to survive (1). This DN3 population can be further subdivided into DN3a and DN3b based on their size and CD27 surface expression.Importantly, DN3a cells (FSC lo CD27 lo ) actively rearrange the genes encoding the T cell receptor β (TCRβ) chain through V(D)J recombination (1-3). Those DN3a cells that do not productively rearrange the TCRβ locus on both alleles are eliminated by apoptosis. In contrast, cells that productively rearrange their TCRβ chain genes are selected and become DN3b cells (FSC hi CD27 hi ), which express a pre-T cell receptor (pre-TCR), a heterodimer between the TCRβ chain and a pTα chain. DN3b cells grow in size, owing in part to increased metabolic activity (4), and give rise to the (CD44 − CD25 − ) DN4 subset, which in turn rapidly expands to produce CD4 + CD8 + DP cells.

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Section: Cd19supporting

confidence: 93%

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination

Rashkovan

Vadnais

Ross

et al. 2014

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

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“…While previous evidence suggested that Rpl22 might play a role during B cell development (19, 22), neither the stages affected nor the mechanistic basis for the impairment of B cell development had been assessed. To begin to understand the role of Rpl22 during B cell development, we analyzed splenic B cells from Rpl22 +/+ and Rpl22 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, the regulation of p53 by Rpl22 is post-transcriptional, as there was no change in p53 mRNA in the absence of Rpl22. While previous studies have suggested a role for Rpl22 during B cell development (19, 22), neither the stages affected nor the underlying mechanism was addressed.…”

Section: Introductionmentioning

confidence: 96%

Rpl22 Loss Impairs the Development of B Lymphocytes by Activating a p53-Dependent Checkpoint

Fahl

Harris

Coffey

et al. 2015

The Journal of Immunology

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While ribosomal proteins facilitate the ribosome’s core function of translation, emerging evidence suggests that some ribosomal proteins are also capable of performing tissue restricted functions either from within specialized ribosomes or from outside of the ribosome. In particular, we have previously demonstrated that germline ablation of the gene encoding ribosomal protein Rpl22 causes a selective and p53 dependent arrest of αβ T cell progenitors at the β-selection checkpoint. We have now identified a crucial role for Rpl22 during early B cell development. Germline ablation of Rpl22 results in a reduction in the absolute number of B-lineage progenitors in the bone marrow beginning at the pro-B cell stage. Although Rpl22-deficient proB cells are hyporesponsive to IL-7, a key cytokine required for early B cell development, the arrest of B cell development does not result from disrupted IL-7 signaling. Instead, p53 induction appears to be responsible for the developmental defects, as Rpl22-deficiency causes increased expression of p53 and activation of downstream p53 target genes and p53-deficiency rescues the defect in B cell development in Rpl22-deficient mice. Interestingly, the requirement for Rpl22 in the B cell lineage appears to be developmentally restricted, since Rpl22-deficient splenic B cells proliferate normally in response to antigen receptor and toll receptor stimuli and undergo normal class switch recombination. These results indicate that Rpl22 performs a critical, developmentally restricted role in supporting early B cell development by preventing p53-induction.

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“…The assembly process requires the nearly simultaneous presence of an equimolar amount of nearly all the 80 RPs. There are two types of exceptions: (1) In yeast, eight of the 79 RPs are not essential for reasonable growth (Steffen et al 2012), and in mammals, a few RPs, such as L22 (O'Leary et al 2013) and L40 (Lee et al 2013) seem to be dispensable for ribosome assembly and for cell growth; none are known to be dispensable for the development of an intact animal; and (2) the stalk proteins, P1 and P2, are present in two copies per ribosome and exchange between a cytoplasmic pool and mature ribosomes (for review, see Gonzalo and Reboud 2003).…”

Section: Introductionmentioning

confidence: 99%

Ribosome-omics of the human ribosome

Gupta

Warner

2014

RNA

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The torrent of RNA-seq data becoming available not only furnishes an overview of the entire transcriptome but also provides tools to focus on specific areas of interest. Our focus on the synthesis of ribosomes asked whether the abundance of mRNAs encoding ribosomal proteins (RPs) matched the equimolar need for the RPs in the assembly of ribosomes. We were at first surprised to find, in the mapping data of ENCODE and other sources, that there were nearly 100-fold differences in the level of the mRNAs encoding the different RPs. However, after correcting for the mapping ambiguities introduced by the presence of more than 2000 pseudogenes derived from RP mRNAs, we show that for 80%-90% of the RP genes, the molar ratio of mRNAs varies less than threefold, with little tissue specificity. Nevertheless, since the RPs are needed in equimolar amounts, there must be sluggish or regulated translation of the more abundant RP mRNAs and/or substantial turnover of unused RPs. In addition, seven of the RPs have subsidiary genes, three of which are pseudogenes that have been "rescued" by the introduction of promoters and/or upstream introns. Several of these are transcribed in a tissue-specific manner, e.g., RPL10L in testis and RPL3L in muscle, leading to potential variation in ribosome structure from one tissue to another. Of the 376 introns in the RP genes, a single one is alternatively spliced in a tissue-specific manner.

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The Ribosomal Protein Rpl22 Controls Ribosome Composition by Directly Repressing Expression of Its Own Paralog, Rpl22l1

Cited by 93 publications

References 80 publications

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination

Rpl22 Loss Impairs the Development of B Lymphocytes by Activating a p53-Dependent Checkpoint

Ribosome-omics of the human ribosome

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