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12 pages, 3432 KiB

Open AccessArticle

Hsp90 Activity Is Necessary for the Maturation of Rabies Virus Polymerase

by Iga Dalidowska, Anna Orlowska, Marcin Smreczak and Pawel Bieganowski

Int. J. Mol. Sci. 2022, 23(13), 6946; https://doi.org/10.3390/ijms23136946 - 22 Jun 2022

Cited by 2 | Viewed by 1579

Abstract

Mononegavirales is an order of viruses with a genome in the form of a non-segmented negative-strand RNA that encodes several proteins. The functional polymerase complex of these viruses is composed of two proteins: a large protein (L) and a phosphoprotein (P). The replication [...] Read more.

Mononegavirales is an order of viruses with a genome in the form of a non-segmented negative-strand RNA that encodes several proteins. The functional polymerase complex of these viruses is composed of two proteins: a large protein (L) and a phosphoprotein (P). The replication of viruses from this order depends on Hsp90 chaperone activity. Previous studies have demonstrated that Hsp90 inhibition results in the degradation of mononegaviruses L protein, with exception of the rabies virus, for which the degradation of P protein was observed. Here, we demonstrated that Hsp90 inhibition does not affect the expression of rabies L and P proteins, but it inhibits binding of the P protein and L protein into functional viral polymerase. Rabies and the vesicular stomatitis virus, but not the measles virus, L proteins can be expressed independently of the presence of a P protein and in the presence of an Hsp90 inhibitor. Our results suggest that the interaction of L proteins with P proteins and Hsp90 in the process of polymerase maturation may be a process specific to particular viruses. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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14 pages, 5891 KiB

Open AccessArticle

Mitochondrial Inhibition by Sodium Azide Induces Assembly of eIF2α Phosphorylation-Independent Stress Granules in Mammalian Cells

by Nina Eiermann, Georg Stoecklin and Bogdan Jovanovic

Int. J. Mol. Sci. 2022, 23(10), 5600; https://doi.org/10.3390/ijms23105600 - 17 May 2022

Cited by 2 | Viewed by 2798

Abstract

Mitochondrial stress is involved in many pathological conditions and triggers the integrated stress response (ISR). The ISR is initiated by phosphorylation of the eukaryotic translation initiation factor (eIF) 2α and results in global inhibition of protein synthesis, while the production of specific proteins [...] Read more.

Mitochondrial stress is involved in many pathological conditions and triggers the integrated stress response (ISR). The ISR is initiated by phosphorylation of the eukaryotic translation initiation factor (eIF) 2α and results in global inhibition of protein synthesis, while the production of specific proteins important for the stress response and recovery is favored. The stalled translation preinitiation complexes phase-separate together with local RNA binding proteins into cytoplasmic stress granules (SG), which are important for regulation of cell signaling and survival under stress conditions. Here we found that mitochondrial inhibition by sodium azide (NaN₃) in mammalian cells leads to translational inhibition and formation of SGs, as previously shown in yeast. Although mammalian NaN₃-induced SGs are very small, they still contain the canonical SG proteins Caprin 1, eIF4A, eIF4E, eIF4G and eIF3B. Similar to FCCP and oligomycine, other mitochodrial stressors that cause SG formation, NaN₃-induced SGs are formed by an eIF2α phosphorylation-independent mechanisms. Finally, we discovered that as shown for arsenite (ASN), but unlike FCCP or heatshock stress, Thioredoxin 1 (Trx1) is required for formation of NaN₃-induced SGs. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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13 pages, 2676 KiB

Open AccessArticle

The Significance of the DUF283 Domain for the Activity of Human Ribonuclease Dicer

by Agnieszka Szczepanska, Marta Wojnicka and Anna Kurzynska-Kokorniak

Int. J. Mol. Sci. 2021, 22(16), 8690; https://doi.org/10.3390/ijms22168690 - 13 Aug 2021

Cited by 4 | Viewed by 2415

Abstract

Dicers are multidomain proteins, usually comprising an amino-terminal putative helicase domain, a DUF283 domain (domain of unknown function), a PAZ domain, two RNase III domains (RNase IIIa and RNase IIIb) and a dsRNA-binding domain. Dicer homologs play an important role in the biogenesis [...] Read more.

Dicers are multidomain proteins, usually comprising an amino-terminal putative helicase domain, a DUF283 domain (domain of unknown function), a PAZ domain, two RNase III domains (RNase IIIa and RNase IIIb) and a dsRNA-binding domain. Dicer homologs play an important role in the biogenesis of small regulatory RNAs by cleaving single-stranded precursors adopting stem-loop structures (pre-miRNAs) and double-strand RNAs into short RNA duplexes containing functional microRNAs or small interfering RNAs, respectively. Growing evidence shows that apart from the canonical role, Dicer proteins can serve a number of other functions. For example, results of our previous studies showed that human Dicer (hDicer), presumably through its DUF283 domain, can facilitate hybridization between two complementary RNAs, thus, acting as a nucleic acid annealer. Here, to test this assumption, we prepared a hDicer deletion variant lacking the amino acid residues 625-752 corresponding to the DUF283 domain. The respective 128-amino acid fragment of hDicer was earlier demonstrated to accelerate base-pairing between two complementary RNAs in vitro. We show that the ΔDUF(625-752) hDicer variant loses the potential to facilitate RNA-RNA base pairing, which strongly proves our hypothesis about the importance of the DUF283 domain for the RNA-RNA annealing activity of hDicer. Interestingly, the in vitro biochemical characterization of the obtained deletion variant reveals that it displays different RNA cleavage properties depending on the pre-miRNA substrate. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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14 pages, 3599 KiB

Open AccessArticle

Arabidopsis thaliana G3BP Ortholog Rescues Mammalian Stress Granule Phenotype across Kingdoms

by Hendrik Reuper, Benjamin Götte, Lucy Williams, Timothy J. C. Tan, Gerald M. McInerney, Marc D. Panas and Björn Krenz

Int. J. Mol. Sci. 2021, 22(12), 6287; https://doi.org/10.3390/ijms22126287 - 11 Jun 2021

Cited by 6 | Viewed by 3529

Abstract

Stress granules (SGs) are dynamic RNA–protein complexes localized in the cytoplasm that rapidly form under stress conditions and disperse when normal conditions are restored. The formation of SGs depends on the Ras-GAP SH3 domain-binding protein (G3BP). Formations, interactions and functions of plant and [...] Read more.

Stress granules (SGs) are dynamic RNA–protein complexes localized in the cytoplasm that rapidly form under stress conditions and disperse when normal conditions are restored. The formation of SGs depends on the Ras-GAP SH3 domain-binding protein (G3BP). Formations, interactions and functions of plant and human SGs are strikingly similar, suggesting a conserved mechanism. However, functional analyses of plant G3BPs are missing. Thus, members of the Arabidopsis thaliana G3BP (AtG3BP) protein family were investigated in a complementation assay in a human G3BP knock-out cell line. It was shown that two out of seven AtG3BPs were able to complement the function of their human homolog. GFP-AtG3BP fusion proteins co-localized with human SG marker proteins Caprin-1 and eIF4G1 and restored SG formation in G3BP double KO cells. Interaction between AtG3BP-1 and -7 and known human G3BP interaction partners such as Caprin-1 and USP10 was also demonstrated by co-immunoprecipitation. In addition, an RG/RGG domain exchange from Arabidopsis G3BP into the human G3BP background showed the ability for complementation. In summary, our results support a conserved mechanism of SG function over the kingdoms, which will help to further elucidate the biological function of the Arabidopsis G3BP protein family. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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11 pages, 3399 KiB

Open AccessArticle

ATP-Independent Initiation during Cap-Independent Translation of m⁶A-Modified mRNA

by Pavel A. Sakharov, Egor A. Smolin, Dmitry N. Lyabin and Sultan C. Agalarov

Int. J. Mol. Sci. 2021, 22(7), 3662; https://doi.org/10.3390/ijms22073662 - 01 Apr 2021

Cited by 3 | Viewed by 2137

Abstract

The methylation of adenosine in the N⁶ position (m⁶A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated [...] Read more.

The methylation of adenosine in the N⁶ position (m⁶A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated in conditions of inhibited cap-dependent translation initiation, e.g., under stress. However, the peculiarities of translation initiation on m⁶A-modified mRNAs are not fully known. In this study, we used toeprinting and translation in a cell-free system to confirm that m⁶A-modified mRNAs can be translated in conditions of suppressed cap-dependent translation. We show for the first time that m⁶A-modified mRNAs display not only decreased elongation, but also a lower efficiency of translation initiation. Additionally, we report relative resistance of m⁶A-mRNA translation initiation in the absence of ATP and inhibited eIF4A activity. Our novel findings indicate that the scanning of m⁶A-modified leader sequences is performed by a noncanonical mechanism. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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Review

Jump to: Research

24 pages, 935 KiB

Open AccessReview

How RNases Shape Mitochondrial Transcriptomes

by Jérémy Cartalas, Léna Coudray and Anthony Gobert

Int. J. Mol. Sci. 2022, 23(11), 6141; https://doi.org/10.3390/ijms23116141 - 30 May 2022

Cited by 5 | Viewed by 2499

Abstract

Mitochondria are the power houses of eukaryote cells. These endosymbiotic organelles of prokaryote origin are considered as semi-autonomous since they have retained a genome and fully functional gene expression mechanisms. These pathways are particularly interesting because they combine features inherited from the bacterial [...] Read more.

Mitochondria are the power houses of eukaryote cells. These endosymbiotic organelles of prokaryote origin are considered as semi-autonomous since they have retained a genome and fully functional gene expression mechanisms. These pathways are particularly interesting because they combine features inherited from the bacterial ancestor of mitochondria with characteristics that appeared during eukaryote evolution. RNA biology is thus particularly diverse in mitochondria. It involves an unexpectedly vast array of factors, some of which being universal to all mitochondria and others being specific from specific eukaryote clades. Among them, ribonucleases are particularly prominent. They play pivotal functions such as the maturation of transcript ends, RNA degradation and surveillance functions that are required to attain the pool of mature RNAs required to synthesize essential mitochondrial proteins such as respiratory chain proteins. Beyond these functions, mitochondrial ribonucleases are also involved in the maintenance and replication of mitochondrial DNA, and even possibly in the biogenesis of mitochondrial ribosomes. The diversity of mitochondrial RNases is reviewed here, showing for instance how in some cases a bacterial-type enzyme was kept in some eukaryotes, while in other clades, eukaryote specific enzymes were recruited for the same function. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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21 pages, 2690 KiB

Open AccessReview

Types and Functions of Mitoribosome-Specific Ribosomal Proteins across Eukaryotes

by Vassilis Scaltsoyiannes, Nicolas Corre, Florent Waltz and Philippe Giegé

Int. J. Mol. Sci. 2022, 23(7), 3474; https://doi.org/10.3390/ijms23073474 - 23 Mar 2022

Cited by 8 | Viewed by 3382

Abstract

Mitochondria are key organelles that combine features inherited from their bacterial endosymbiotic ancestor with traits that arose during eukaryote evolution. These energy producing organelles have retained a genome and fully functional gene expression machineries including specific ribosomes. Recent advances in cryo-electron microscopy have [...] Read more.

Mitochondria are key organelles that combine features inherited from their bacterial endosymbiotic ancestor with traits that arose during eukaryote evolution. These energy producing organelles have retained a genome and fully functional gene expression machineries including specific ribosomes. Recent advances in cryo-electron microscopy have enabled the characterization of a fast-growing number of the low abundant membrane-bound mitochondrial ribosomes. Surprisingly, mitoribosomes were found to be extremely diverse both in terms of structure and composition. Still, all of them drastically increased their number of ribosomal proteins. Interestingly, among the more than 130 novel ribosomal proteins identified to date in mitochondria, most of them are composed of a-helices. Many of them belong to the nuclear encoded super family of helical repeat proteins. Here we review the diversity of functions and the mode of action held by the novel mitoribosome proteins and discuss why these proteins that share similar helical folds were independently recruited by mitoribosomes during evolution in independent eukaryote clades. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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18 pages, 2870 KiB

Open AccessReview

Activity and Function in Human Cells of the Evolutionary Conserved Exonuclease Polynucleotide Phosphorylase

by Federica A. Falchi, Roberto Pizzoccheri and Federica Briani

Int. J. Mol. Sci. 2022, 23(3), 1652; https://doi.org/10.3390/ijms23031652 - 31 Jan 2022

Cited by 7 | Viewed by 3402

Abstract

Polynucleotide phosphorylase (PNPase) is a phosphorolytic RNA exonuclease highly conserved throughout evolution. Human PNPase (hPNPase) is located in mitochondria and is essential for mitochondrial function and homeostasis. Not surprisingly, mutations in the PNPT1 gene, encoding hPNPase, cause serious diseases. hPNPase has been implicated [...] Read more.

Polynucleotide phosphorylase (PNPase) is a phosphorolytic RNA exonuclease highly conserved throughout evolution. Human PNPase (hPNPase) is located in mitochondria and is essential for mitochondrial function and homeostasis. Not surprisingly, mutations in the PNPT1 gene, encoding hPNPase, cause serious diseases. hPNPase has been implicated in a plethora of processes taking place in different cell compartments and involving other proteins, some of which physically interact with hPNPase. This paper reviews hPNPase RNA binding and catalytic activity in relation with the protein structure and in comparison, with the activity of bacterial PNPases. The functions ascribed to hPNPase in different cell compartments are discussed, highlighting the gaps that still need to be filled to understand the physiological role of this ancient protein in human cells. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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15 pages, 814 KiB

Open AccessReview

Functions of PPR Proteins in Plant Growth and Development

by Xiulan Li, Mengdi Sun, Shijuan Liu, Qian Teng, Shihui Li and Yueshui Jiang

Int. J. Mol. Sci. 2021, 22(20), 11274; https://doi.org/10.3390/ijms222011274 - 19 Oct 2021

Cited by 26 | Viewed by 4283

Abstract

Pentatricopeptide repeat (PPR) proteins form a large protein family in land plants, with hundreds of different members in angiosperms. In the last decade, a number of studies have shown that PPR proteins are sequence-specific RNA-binding proteins involved in multiple aspects of plant organellar [...] Read more.

Pentatricopeptide repeat (PPR) proteins form a large protein family in land plants, with hundreds of different members in angiosperms. In the last decade, a number of studies have shown that PPR proteins are sequence-specific RNA-binding proteins involved in multiple aspects of plant organellar RNA processing, and perform numerous functions in plants throughout their life cycle. Recently, computational and structural studies have provided new insights into the working mechanisms of PPR proteins in RNA recognition and cytidine deamination. In this review, we summarized the research progress on the functions of PPR proteins in plant growth and development, with a particular focus on their effects on cytoplasmic male sterility, stress responses, and seed development. We also documented the molecular mechanisms of PPR proteins in mediating RNA processing in plant mitochondria and chloroplasts. Full article

(This article belongs to the Special Issue Research Progress in RNA-Binding Proteins)

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