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Abstract
Ribosomes are the highly complex macromolecular assemblies dedicated to the synthesis of all cellular proteins from mRNA templates. The main principles underlying the making of ribosomes are conserved across eukaryotic organisms and this process has been studied in most detail in the yeast Saccharomyces cerevisiae. Yeast ribosomes are composed of four ribosomal RNAs (rRNAs) and 79 ribosomal proteins (r-proteins). Most r-proteins need to be transported from the cytoplasm to the nucleus where they get incorporated into the evolving pre-ribosomal particles. Due to the high abundance and difficult physicochemical properties of r-proteins, their correct folding and fail-safe targeting to the assembly site depends largely on general, as well as highly specialized, chaperone and transport systems. Many r-proteins contain universally conserved or eukaryote-specific internal loops and/or terminal extensions, which were shown to mediate their nuclear targeting and association with dedicated chaperones in a growing number of cases. The 60S r-protein Rpl4 is particularly interesting since it harbours a conserved long internal loop and a prominent C-terminal eukaryote-specific extension. Here we show that both the long internal loop and the C-terminal eukaryote-specific extension are strictly required for the functionality of Rpl4. While Rpl4 contains at least five distinct nuclear localization signals (NLS), the C-terminal part of the long internal loop associates with a specific binding partner, termed Acl4. Absence of Acl4 confers a severe slow-growth phenotype and a deficiency in the production of 60S subunits. Genetic and biochemical evidence indicates that Acl4 can be considered as a dedicated chaperone of Rpl4. Notably, Acl4 localizes to both the cytoplasm and nucleus and it has the capacity to capture nascent Rpl4 in a co-translational manner. Taken together, our findings indicate that the dedicated chaperone Acl4 accompanies Rpl4 from the cytoplasm to its pre-60S assembly site in the nucleus.
Highlights
The biogenesis of ribosomes is a fundamental cellular process whose main principles are conserved from the lower eukaryote Saccharomyces cerevisiae to mammalian organisms
The synthesis of ribosomes basically consists in the ordered assembly of the r-proteins with the ribosomal RNAs (rRNAs); the efficient and accurate assembly of r-subunits vitally depends on a multitude (>200) of transiently acting biogenesis factors [2,3,4,5]
The first pre-60S ribosome, termed 66S particle, assembles on nascent pre-rRNA and contains, upon termination of transcription, the 27SA2 pre-rRNA [2,8]. This 66S pre-ribosomal particle is associated with selected r-proteins, mainly binding to domains I and II of 25S rRNA, that promote the initial compaction of the emerging LSU and a characteristic set of early-acting biogenesis factors [2,3,11]
Summary
The biogenesis of ribosomes is a fundamental cellular process whose main principles are conserved from the lower eukaryote Saccharomyces cerevisiae to mammalian organisms. In a predominantly co-transcriptional process, the pre-rRNA within this initial pre-ribosomal particle undergoes cleavage at processing site A2 (for a pre-rRNA processing scheme, see S1 Fig) [7,8], leading to the formation of nuclear 43S pre-ribosomal particles containing the 20S pre-rRNA These pre-40S ribosomes are rapidly exported to the cytoplasm, where they are converted in a series of concerted events, including processing of 20S pre-rRNA to 18S rRNA, into mature 40S subunits [2,3,4,5,9,10]. The first pre-60S ribosome, termed 66S particle, assembles on nascent pre-rRNA and contains, upon termination of transcription, the 27SA2 pre-rRNA [2,8] This 66S pre-ribosomal particle is associated with selected r-proteins, mainly binding to domains I and II of 25S rRNA, that promote the initial compaction of the emerging LSU and a characteristic set of early-acting biogenesis factors [2,3,11]. Maturation of and pre-rRNA processing within nuclear pre-60S particles proceeds in a hierarchical manner and involves the sequential recruitment of r-proteins, which shape and stabilize the pre-60S subunit with the aid of specific biogenesis factors
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