Genome-Wide Polysome Profiling Reveals an Inflammation-Responsive Posttranscriptional Operon in Gamma Interferon-Activated Monocytes

Vyas, Keyur; Chaudhuri, Sujan; Leaman, Douglas W.; Komar, Anton A.; Musiyenko, Alla; Barik, Sailen; Mazumder, Barsanjit

doi:10.1128/mcb.00824-08

Cited by 77 publications

(103 citation statements)

References 43 publications

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“…Another demonstrated function of L13a occurs outside the ribosome. We (11,13) and others (36) have shown that the phosphorylation-dependent release of L13a from 60S subunits in response to extracellular stimuli, such as IFN-␥ treatment, leads to incorporation of L13a into the socalled GAIT complex (11,13,55) and translational silencing of a cohort of mRNAs harboring GAIT elements in their 3=-UTRs (12). Here, we show that the mechanisms of incorporation of L13a protein into the ribosome and into the GAIT complex are distinct.…”

Section: Figmentioning

confidence: 48%

“…We previously defined an extraribosomal activity of L13a: IFN-␥-induced translational silencing of a cohort of mRNAs encoding inflammatory proteins and containing a GAIT element in their 3=-UTRs (11,12,33,34). This activity requires phosphorylationmediated release of L13a from the 60S ribosomal subunit, which occurs in response to IFN-␥ (13,35).…”

Section: Resultsmentioning

confidence: 99%

“…L13a is known to be a component of the 60S ribosomal subunit and to be present in mature 80S ribosomes; however, its function within the ribosome remains unknown. Nevertheless we have demonstrated that L13a has an important extraribosomal function: translational silencing of a cohort of inflammatory proteins in gamma interferon (IFN-␥)-activated human monocytic U937 cells (11,12). We demonstrated that this extraribosomal function requires phosphorylation-mediated release of L13a from the 60S ribosomal subunit.…”

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confidence: 97%

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Insights into the Mechanism of Ribosomal Incorporation of Mammalian L13a Protein during Ribosome Biogenesis

Das

Basu

Biswas

et al. 2013

Molecular and Cellular Biology

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bIn contrast to prokaryotes, the precise mechanism of incorporation of ribosomal proteins into ribosomes in eukaryotes is not well understood. For the majority of eukaryotic ribosomal proteins, residues critical for rRNA binding, a key step in the hierarchical assembly of ribosomes, have not been well defined. In this study, we used the mammalian ribosomal protein L13a as a model to investigate the mechanism(s) underlying eukaryotic ribosomal protein incorporation into ribosomes. This work identified the arginine residue at position 68 of L13a as being essential for L13a binding to rRNA and incorporation into ribosomes. We also demonstrated that incorporation of L13a takes place during maturation of the 90S preribosome in the nucleolus, but that translocation of L13a into the nucleolus is not sufficient for its incorporation into ribosomes. Incorporation of L13a into the 90S preribosome was required for rRNA methylation within the 90S complex. However, mutations abolishing ribosomal incorporation of L13a did not affect its ability to be phosphorylated or its extraribosomal function in GAIT element-mediated translational silencing. These results provide new insights into the mechanism of ribosomal incorporation of L13a and will be useful in guiding future studies aimed at fully deciphering mammalian ribosome biogenesis. Ribosome biogenesis is an essential and highly complex process in all living organisms. Ribosomes are composed of numerous precisely assembled proteins and rRNA molecules; thus, they present a paradigm for RNA-protein recognition/binding and ribonucleoprotein (RNP) folding. In prokaryotes, the highly ordered process of ribosome assembly is relatively well defined and has been shown to involve orchestrated changes in rRNA conformation and protein binding steps (1). In contrast, very little is known about the mechanism of eukaryotic ribosome assembly. Despite the general similarity of eukaryotic and prokaryotic ribosomes, they differ substantially in their size, structure, and subunit compositions (including the numbers and sequences of proteins and rRNAs). Another key difference is that the process of maturation and assembly of eukaryotic ribosomes is a highly compartmentalized process which starts in the nucleolus and finishes in the cytoplasm (2). Factors that are not ribosome components but are involved in the ribosome maturation and assembly process also may differ between prokaryotes and eukaryotes. Production of eukaryotic ribosomes (including export from the nucleolus into the cytoplasm) requires highly synchronized synthesis of four rRNAs, about 80 ribosomal proteins, 150 proteins that serve as assembly factors, and 70 small nucleolar RNAs (snoRNAs) that direct modifications to rRNAs (3, 4). Advances in affinity purification methods using epitope-tagged proteins and mass spectrometry have allowed molecular characterization of several distinct RNP complexes corresponding to nucleolar preribosomes at different stages of assembly (5-7). However, this information was primarily derived from stud...

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Section: Figmentioning

confidence: 48%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 97%

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Insights into the Mechanism of Ribosomal Incorporation of Mammalian L13a Protein during Ribosome Biogenesis

Das

Basu

Biswas

et al. 2013

Molecular and Cellular Biology

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“…Loss of RPS25 also resulted in inhibition of viral IRES-based translation, though not cap-dependent cellular translation [43]. The interferon-gamma regulated release of RPL13a from the ribosome is also postulated to impact the translation of around 50 genes [44,45]. These findings argue for a very high degree of specificity.…”

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confidence: 99%

Ribosome stoichiometry: from form to function.

Emmott

Jovanović

Slavov

2018

Preprint

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The existence of eukaryotic ribosomes with distinct ribosomal protein (RP) stoichiometry and regulatory roles in protein synthesis been speculated for over sixty years. Recent advances in mass spectrometry and high throughput analysis have begun to identify and characterize distinct ribosome stoichiometry in yeast or mammalian systems. In addition to RP stoichiometry, ribosomes play host to a vast array of protein modifications, effectively expanding the number of human RPs from 80 to many thousands of distinct proteoforms. Is it possible these proteoforms combine to function as a 'ribosome code' to tune protein synthesis? We outline the specific benefits that translational regulation by specialized ribosomes can offer and discuss the means and methodologies available to correlate and characterize RP stoichiometry with function. We highlight previous research with a focus on formulating hypotheses that can guide future experiments and crack the 'ribosome code'.Ribosomes, the cellular machinery of protein synthesis, are present at up to ten million copies per cell in mammals. Despite their abundance and the wide array of known modifications to both ribosomal proteins (RPs) and rRNA, study of the direct role of the ribosome in tuning cellular translation has until recently taken a back seat to posttranscriptional regulation at the level of translation initiation. The hypothesis that ribosomes actively regulate protein synthesis as part of normal development and physiology dates back to the 1950s [1]. In the ensuing decades, numerous albeit inconclusive, observations have supported this hypothesis, and a subset of those are shown in Figure 1, color-coded by the type of evidence.For many years, the dominant 'abundance' model of translational regulation by the ribosome suggested a limited role for ribosomes in translation regulation [2]. In this model, if ribosomes have different initiation affinity for different transcripts, a global decrease in the availability of free ribosomes selectively decreases the initiation rates of different transcripts to varying degrees [2]. This mechanism, recently reviewed by Mills and Green [4], relies on the non-linear dependence of translation initiation on free ribosomes and applies quite generally. Indeed, recent research from the Sankaran lab suggested this mechanisms could explain the failure of erythroid lineage commitment seen with Diamond-Blackfan anaemia [5] 2 by the abundance model is limited in magnitude by the changes of total ribosomal content and in flexibility since it provides unidirectional regulation for all proteins.The concept of ribosome specialization In the 'specialized' ribosome model, ribosomes do not possess constant structure or composition (Figure 2A, B), and instead exhibit altered stoichiometry of what were previously thought to represent 'core' ribosomal proteins (Figure 1) [7,8]. In this model, different ribosomal compositions are functional and have specific roles in translation. Specialized ribosomes could co-exist within cells, or between ...

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“…This GAIT element is a cis-acting RNA element first identified in the 3 -UTR of the ceruloplasmin (Cp) mRNA in humans. In a more general way, GAIT elements have been found in several immune-related mRNAs showing an important role in gene-specific translation control in innate immunity (Vyas et al, 2009). These elements form a stem-loop structure that is involved in the selective translational silencing of mRNA transcripts.…”

Section: Discussionmentioning

confidence: 99%

LPS injection reprograms the expression and the 3′ UTR of a CAP gene by alternative polyadenylation and the formation of a GAIT element in Ciona intestinalis

Vizzini¹,

Bonura

Longo

et al. 2016

Molecular Immunology

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a b s t r a c tThe diversification of cellular functions is one of the major characteristics of multicellular organisms which allow cells to modulate their gene expression, leading to the formation of transcripts and proteins with different functions and concentrations in response to different stimuli. CAP genes represent a widespread family of proteins belonging to the cysteine-rich secretory protein, antigen 5 and pathogenesis-related 1 superfamily which, it has been proposed, play key roles in the infection process and the modulation of immune responses in host animals. The ascidian Ciona intestinalis represents a group of proto-chordates with an exclusively innate immune system that has been widely studied in the field of comparative and developmental immunology. Using this biological system, we describe the identification of a novel APA mechanism by which an intronic polyadenylation signal is activated by LPS injection, leading to the formation of a shorter CAP mRNA capable of expressing the first CAP exon plus 19 amino acid residues whose sequence is contained within the first intron of the annotated gene. Furthermore, such an APA event causes the expression of a translational controlling cis-acting GAIT element which is not present in the previously isolated CAP isoform and identified in the 3 -UTR of other immunerelated genes, suggesting an intriguing scenario in which both transcriptional and post-transcriptional control mechanisms are involved in the activation of the CAP gene during inflammatory response in C. intestinalis.

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Genome-Wide Polysome Profiling Reveals an Inflammation-Responsive Posttranscriptional Operon in Gamma Interferon-Activated Monocytes

Cited by 77 publications

References 43 publications

Insights into the Mechanism of Ribosomal Incorporation of Mammalian L13a Protein during Ribosome Biogenesis

Insights into the Mechanism of Ribosomal Incorporation of Mammalian L13a Protein during Ribosome Biogenesis

Ribosome stoichiometry: from form to function.

LPS injection reprograms the expression and the 3′ UTR of a CAP gene by alternative polyadenylation and the formation of a GAIT element in Ciona intestinalis

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