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Yar1 Protects the Ribosomal Protein Rps3 from Aggregation*

Open AccessPublished:May 08, 2012DOI:https://doi.org/10.1074/jbc.M112.365791
      2000 ribosomes have to be synthesized in yeast every minute. Therefore the fast production of ribosomal proteins, their efficient delivery to the nucleus and correct incorporation into ribosomal subunits are prerequisites for optimal growth rates. Here, we report that the ankyrin repeat protein Yar1 directly interacts with the small ribosomal subunit protein Rps3 and accompanies newly synthesized Rps3 from the cytoplasm into the nucleus where Rps3 is assembled into pre-ribosomal subunits. A yar1 deletion strain displays a similar phenotype as an rps3 mutant strain, showing an accumulation of 20S pre-rRNA and a 40S export defect. The combination of an rps3 mutation with a yar1 deletion leads to an enhancement of these phenotypes, while increased expression of RPS3 suppresses the defects of a yar1 deletion strain. We further show that Yar1 protects Rps3 from aggregation in vitro and increases its solubility in vivo. Our data suggest that Yar1 is a specific chaperone for Rps3, which serves to keep Rps3 soluble until its incorporation into the pre-ribosome.

      Introduction

      The synthesis of ribosomes is one of the major activities of a eukaryotic cell involving the action of almost 200 trans-acting factors that participate in the formation of a large 60S and a small 40S subunit (
      • Warner J.R.
      The economics of ribosome biosynthesis in yeast.
      ). The challenge of this process is to correctly assemble one (in the case of 40S) to three (60S) ribosomal RNAs (rRNAs)
      The abbreviations used are: rRNA
      ribosomal RNA
      TAP
      tandem affinity purification
      TEV
      tobacco etch virus
      5-FOA
      5-fluoroorotic acid
      ITS
      internal transcribed spacer
      LMB
      leptomycin B
      NLS
      nuclear localization sequence
      pre-rRNA
      precursor rRNA
      SDC
      synthetic dextrose complete
      CBP
      calmodulin-binding protein.
      and many different ribosomal proteins to form a complexly structured molecular machine, which is capable of accurately translating the genetic code into the amino acid sequence of proteins.
      In the biogenesis pathway, a common precursor particle for the small and large ribosomal subunits is formed in the nucleolus, the 90S particle, containing the 35S pre-rRNA or processed versions thereof, ribosomal proteins and a large number of non-ribosomal factors. This precursor undergoes a complex series of protein assembly and disassembly as well as rRNA processing (see Fig. 5A) and modification events. During these maturation steps, an rRNA cleavage event separates the common precursor into a pre-40S and pre-60S particle. These particles independently undergo further maturation events, which do not only take place in the nucleolus and the nucleoplasm, but also following nuclear export of pre-ribosomal particles, within the cytoplasm. For recent reviews on ribosome biogenesis see Refs.
      • Henras A.K.
      • Soudet J.
      • Gérus M.
      • Lebaron S.
      • Caizergues-Ferrer M.
      • Mougin A.
      • Henry Y.
      The post-transcriptional steps of eukaryotic ribosome biogenesis.
      ,
      • Kressler D.
      • Hurt E.
      • Bassler J.
      Driving ribosome assembly.
      ,
      • Strunk B.S.
      • Karbstein K.
      Powering through ribosome assembly.
      ,
      • Karbstein K.
      Inside the 40S ribosome assembly machinery.
      ,
      • Panse V.G.
      • Johnson A.W.
      Maturation of eukaryotic ribosomes: acquisition of functionality.
      .
      Figure thumbnail gr5
      FIGURE 5yar1 and rps3 mutants accumulate 20S pre-rRNA. A, simplified rRNA processing pathway in yeast. Only the major pathway for generation of the 5′-end of the 5.8S rRNA is shown. The rRNA cleavage sites and the binding sites of the probes used for Northern blotting are indicated. ITS1 and 2: Internal transcribed spacers 1 and 2. In the course of pre-rRNA processing, the 35S pre-rRNA undergoes a series of endonucleolytic processing events at sites A0, A1, and A2 that lead to the separation of the 20S and 27SA2 pre-rRNAs. Endo- and exonucleolytic processing steps of the 27SA2 pre-rRNA finally yield the mature 25S and 5.8S rRNAs contained in 60S subunits. In the cytoplasm, the final processing step in 40S maturation takes place when the 20S pre-rRNA is converted into the 18S rRNA by endonucleolytic cleavage at processing site D. The aberrant 23S RNA, which is generated by premature cleavage of the 35S pre-rRNA at site A3 is not shown. B, steady-state levels of pre-rRNA and mature rRNA in yar1 and rps3 mutants. Cells were grown at 25 °C or 30 °C to an A600 of 0.6. RNA was isolated, separated by agarose gel electrophoresis, and transferred to a nylon membrane. Pre-rRNA processing intermediates were detected by Northern blotting using the following probes: “A2/A3” for detection of 35S, 33S/32S, 27SA2, and 23S RNAs, “E/C2” for detection of 27SA+B (27SA2, 27SA3 and 27SB) and 7S pre-rRNAs, “D/A2” for detection of the 20S pre-rRNA. Sequences of the probes are given in “Experimental Procedures”; binding sites of the probes are indicated in A.
      In addition to trans-acting factors, ribosomal proteins themselves also participate in ribosome biogenesis (
      • Ferreira-Cerca S.
      • Pöll G.
      • Gleizes P.E.
      • Tschochner H.
      • Milkereit P.
      Roles of eukaryotic ribosomal proteins in maturation and transport of pre-18S rRNA and ribosome function.
      ,
      • Pöll G.
      • Braun T.
      • Jakovljevic J.
      • Neueder A.
      • Jakob S.
      • Woolford Jr., J.L.
      • Tschochner H.
      • Milkereit P.
      rRNA maturation in yeast cells depleted of large ribosomal subunit proteins.
      ). The exact roles of ribosomal proteins in this process still remain to be resolved, however, it is likely that the timely association of ribosomal proteins to the emerging ribosomal subunits is necessary to maintain and presumably also to form the correct tertiary structure of the rRNA.
      Most ribosomal proteins join pre-ribosomal particles early in the ribosome biogenesis pathway, which necessitates transport from their translation site in the cytoplasm to their assembly site in the nucleus. While research on ribosome biogenesis has mostly focused on the maturation steps of pre-ribosomal particles, less is known about the path of newly translated ribosomal proteins to their incorporation site. Nuclear import of ribosomal proteins has been proposed to be mainly mediated by the importin Kap123 (
      • Rout M.P.
      • Blobel G.
      • Aitchison J.D.
      A distinct nuclear import pathway used by ribosomal proteins.
      ). Beside their function as import receptors, importins have been reported to exert a stabilizing function on positively charged import substrates such as histones and ribosomal proteins (
      • Jäkel S.
      • Mingot J.M.
      • Schwarzmaier P.
      • Hartmann E.
      • Görlich D.
      Importins fulfil a dual function as nuclear import receptors and cytoplasmic chaperones for exposed basic domains.
      ). Furthermore, the yeast Hsp70/Hsp40 chaperone system SSB-RAC, known to be engaged in co-translational folding of proteins and the nascent polypeptide-associated complex NAC were proposed to function in preventing ribosomal proteins and ribosome assembly intermediates from aggregation (
      • Koplin A.
      • Preissler S.
      • Ilina Y.
      • Koch M.
      • Scior A.
      • Erhardt M.
      • Deuerling E.
      A dual function for chaperones SSB-RAC and the NAC nascent polypeptide-associated complex on ribosomes.
      ,
      • Karbstein K.
      Chaperoning ribosome assembly.
      ).
      We are studying the yeast 40S ribosomal subunit protein Rps3 as a model to investigate the path of ribosomal proteins from their translation site in the cytoplasm to their assembly site. Like most ribosomal proteins, Rps3 joins pre-ribosomal particles in the nucleus. Failure of Rps3 assembly results in late 40S maturation defects such as 40S export defects and the accumulation of 20S pre-rRNA (
      • Ferreira-Cerca S.
      • Pöll G.
      • Gleizes P.E.
      • Tschochner H.
      • Milkereit P.
      Roles of eukaryotic ribosomal proteins in maturation and transport of pre-18S rRNA and ribosome function.
      ). Initially, Rps3 is only weakly associated to pre-40S particles. It only becomes stably incorporated during a structural re-arrangement of helix 33 of the 18S rRNA. This leads to the formation of the characteristic protrusion of 40S subunits termed the “beak structure” (
      • Schäfer T.
      • Maco B.
      • Petfalski E.
      • Tollervey D.
      • Böttcher B.
      • Aebi U.
      • Hurt E.
      Hrr25-dependent phosphorylation state regulates organization of the pre-40S subunit.
      ). Non-ribosomal binding partners of Rps3 include the pre-40S components Ltv1 and Enp1, as well as the ankyrin repeat protein Yar1 (
      • Schäfer T.
      • Maco B.
      • Petfalski E.
      • Tollervey D.
      • Böttcher B.
      • Aebi U.
      • Hurt E.
      Hrr25-dependent phosphorylation state regulates organization of the pre-40S subunit.
      ,
      • Loar J.W.
      • Seiser R.M.
      • Sundberg A.E.
      • Sagerson H.J.
      • Ilias N.
      • Zobel-Thropp P.
      • Craig E.A.
      • Lycan D.E.
      Genetic and biochemical interactions among Yar1, Ltv1, and Rps3 define novel links between environmental stress and ribosome biogenesis in Saccharomyces cerevisiae.
      ).
      Here, we report that Yar1 directly interacts with Rps3 in vitro and in vivo in a ribosome-free complex. Yar1 localizes to the cytoplasm and the nucleus and is exported in an Xpo1-dependent manner. Although Yar1 is non-essential, it becomes particularly important when Rps3 is not fully functional. Its absence results in 20S pre-rRNA processing and 40S export defects. We further show that in vivo and in vitro, Yar1 increases the solubility of Rps3. Our data suggest that Yar1 is a specific chaperone for Rps3, which accompanies Rps3 from the cytoplasm into the nucleus and maintains its solubility until incorporation into evolving ribosomal subunits.

      DISCUSSION

      The constant supply of ribosomal proteins is crucial for a growing cell to maintain a maximal rate of ribosome synthesis. Hence, it is conceivable that mechanisms exist which ensure that ribosomal proteins are not only synthesized in high amounts, but also remain soluble and are efficiently targeted to the ribosome. In this study, we discovered an anti-aggregation function of the non-ribosomal protein Yar1, which it exhibits exclusively on the small ribosomal subunit protein Rps3. Hence we suggest that Yar1 functions as a specific chaperone for Rps3.
      Because of their extensive interactions with ribosomal RNA, ribosomal proteins usually contain a high proportion of positive charges, which are known to cause aggregation in the presence of polyanions such as RNA (
      • Jäkel S.
      • Mingot J.M.
      • Schwarzmaier P.
      • Hartmann E.
      • Görlich D.
      Importins fulfil a dual function as nuclear import receptors and cytoplasmic chaperones for exposed basic domains.
      ). Yar1 is composed of two ankyrin repeats. Ankyrin repeats are helix-turn-helix motifs of 33 amino acid residues that exhibit an L-shaped topology and exclusively function in mediating protein-protein interactions (
      • Li J.
      • Mahajan A.
      • Tsai M.D.
      Ankyrin repeat: a unique motif mediating protein-protein interactions.
      ). Since Yar1 is a small protein (22 kDa) that does not contain any further domains, it is likely that the main function of Yar1 is to bind Rps3, thereby preventing its aggregation. Protection from aggregation with RNA could be achieved by shielding the positive charges of the basic Rps3 protein (pI 10.2). It is tempting to speculate that Yar1 could act as an RNA mimic for Rps3 considering the high content of negative charges (pI 4.2) found in Yar1.
      Newly translated Rps3 travels from the cytoplasm through the nuclear pores and into the nucleus where it assembles with pre-ribosomal particles. Therefore, it needs to be protected from aggregation along this entire path. Consistently, we found that Yar1 is localized both in the cytoplasm and the nucleus. Yar1 shows a predominantly cytoplasmic steady-state localization, however accumulation is observed in the nucleus after inhibition of the export receptor Xpo1. This is in contrast to previous data from the Lycan laboratory, where nuclear accumulation of Yar1-GFP was not observed upon leptomycin B treatment of an LMB-sensitive xpo1 mutant (
      • Seiser R.M.
      • Sundberg A.E.
      • Wollam B.J.
      • Zobel-Thropp P.
      • Baldwin K.
      • Spector M.D.
      • Lycan D.E.
      Ltv1 is required for efficient nuclear export of the ribosomal small subunit in Saccharomyces cerevisiae.
      ). An explanation for this discrepancy may be that Seiser et al. used a wild-type strain containing Yar1-GFP on a plasmid, probably resulting in competition between the chromosomal wild-type copy and plasmid encoded GFP-tagged Yar1. According to our data, Yar1 is a shuttling protein that binds Rps3 in the cytoplasm and is presumably imported into the nucleus in complex with Rps3, possibly via the N-terminal NLS of Rps3. The low amount of Yar1 detected in the nucleus under steady-state conditions indicates that it is quickly exported into the cytoplasm after dissociation from Rps3, where it can encounter a new Rps3 molecule (Fig. 8).
      Figure thumbnail gr8
      FIGURE 8Model for the function of Yar1. Newly translated Rps3 is bound by Yar1, which shields the positive charges of Rps3 (symbolized in red). After translocation of Yar1 and Rps3 into the nucleus the Yar1-Rps3 complex is disassembled and Rps3 joins pre-ribosomal particles. After its dissociation from Rps3, Yar1 is exported back into the cytoplasm.
      Apparently, the requirement for Yar1 is indirectly proportional to the cellular concentration of Rps3: When Rps3 levels are high, the function of Yar1 is not required for optimal growth. This is probably because sufficient soluble Rps3 is present in the cell to reach pre-ribosomal particles even in the absence of a chaperone. When wild-type levels of Rps3 are expressed, the absence of Yar1 reduces the amount of soluble Rps3, resulting in 40S export defects and a reduced production of mature 40S subunits, eventually leading to reduced growth rates. When Rps3 is not fully functional (as in the case of the rps3-1 mutant), the absence of Yar1 is lethal. This may be due to an insufficient amount of Rps3 reaching pre-ribosomal particles in order to ensure synthesis of the critical number of 40S subunits necessary for growth.
      Recent reports have highlighted the importance of the general chaperone network in assisting ribosome biogenesis (reviewed in Ref.
      • Karbstein K.
      Chaperoning ribosome assembly.
      ). Ribosomal proteins and ribosome biogenesis factors have been found in aggregates in strains deleted for the Hsp70 chaperone SSB (
      • Koplin A.
      • Preissler S.
      • Ilina Y.
      • Koch M.
      • Scior A.
      • Erhardt M.
      • Deuerling E.
      A dual function for chaperones SSB-RAC and the NAC nascent polypeptide-associated complex on ribosomes.
      ). Furthermore, Zuo1, which is involved in stimulation of SSB, and its homologue Jjj1 have been shown to bind to pre-ribosomal particles and participate in ribosome biogenesis (
      • Demoinet E.
      • Jacquier A.
      • Lutfalla G.
      • Fromont-Racine M.
      The Hsp40 chaperone Jjj1 is required for the nucleo-cytoplasmic recycling of preribosomal factors in Saccharomyces cerevisiae.
      ,
      • Meyer A.E.
      • Hung N.J.
      • Yang P.
      • Johnson A.W.
      • Craig E.A.
      The specialized cytosolic J-protein, Jjj1, functions in 60S ribosomal subunit biogenesis.
      ,
      • Meyer A.E.
      • Hoover L.A.
      • Craig E.A.
      The cytosolic J-protein, Jjj1, and Rei1 function in the removal of the pre-60S subunit factor Arx1.
      ,
      • Albanèse V.
      • Reissmann S.
      • Frydman J.
      A ribosome-anchored chaperone network that facilitates eukaryotic ribosome biogenesis.
      ). However, the exact role of the general chaperone network in ribosome biogenesis remains unclear, and as to date, no direct substrates have been described. Additionally, importins have been shown to protect the human ribosomal proteins S7, S3a, L4, L6, and L18a from aggregation with RNA and were suggested to function as general chaperones for ribosomal proteins (
      • Jäkel S.
      • Mingot J.M.
      • Schwarzmaier P.
      • Hartmann E.
      • Görlich D.
      Importins fulfil a dual function as nuclear import receptors and cytoplasmic chaperones for exposed basic domains.
      ).
      The existence of a specific anti-aggregation factor for Rps3 suggests that for some proteins, the general chaperone network of the cell is insufficient for production of the required amounts of soluble protein. The need for additional, more specific factors makes particular sense for ribosomal proteins, which are not only highly expressed but beyond that also prone to aggregation. For these reasons, it is likely that Rps3 is not the only ribosomal protein with a specific chaperone. Chaperone-like functions have also been suggested for Rrb1, a non-ribosomal binding partner of the ribosomal protein Rpl3, Sqt1, an assembly factor for the ribosomal protein Rpl10, as well as Rpf2 and Rrs1, which are involved in the recruitment of 5S rRNA and the ribosomal proteins Rpl5 and Rpl11 into pre-60S subunits (
      • Schaper S.
      • Fromont-Racine M.
      • Linder P.
      • de la Cruz J.
      • Namane A.
      • Yaniv M.
      A yeast homolog of chromatin assembly factor 1 is involved in early ribosome assembly.
      ,
      • Iouk T.L.
      • Aitchison J.D.
      • Maguire S.
      • Wozniak R.W.
      Rrb1p, a yeast nuclear WD-repeat protein involved in the regulation of ribosome biosynthesis.
      ,
      • Eisinger D.P.
      • Dick F.A.
      • Denke E.
      • Trumpower B.L.
      SQT1, which encodes an essential WD domain protein of Saccharomyces cerevisiae, suppresses dominant-negative mutations of the ribosomal protein gene QSR1.
      ,
      • Zhang J.
      • Harnpicharnchai P.
      • Jakovljevic J.
      • Tang L.
      • Guo Y.
      • Oeffinger M.
      • Rout M.P.
      • Hiley S.L.
      • Hughes T.
      • Woolford Jr., J.L.
      Assembly factors Rpf2 and Rrs1 recruit 5S rRNA and ribosomal proteins rpL5 and rpL11 into nascent ribosomes.
      ). It remains open to future investigations to address whether similar aggregation-preventing mechanisms also exist for other ribosomal proteins.

      Acknowledgments

      We thank Lisa Kappel for helpful suggestions, Marén Gnädig for generation of the Yar1-TAP and Yar1-GFP strain, Ed Hurt for providing plasmids, and Matthias Seedorf and Giorgio Dieci for providing antibodies.

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