bims-tricox 2023-01-22 papers

Issue of 2023‒01‒22
six papers selected by
Yash Verma
University of Delhi South Campus

Postepy Biochem. 2022 12 31. 68(4): 425-433

Ribosome heterogeneity as a new element of translation regulation

Piotr J Pietras, Katarzyna Kamińska, Sebastian Pęcherz, Julia Sobkowiak, Kamilla Grzywacz.

All living cells depend on the fine-tuning of gene expression and protein biosynthesis. Ribosomes, the molecular machines at the center of translation, have been previously considered the invariable driving force of protein production. However, recent studies indicated that the ribosomes are actively involved in the regulation of translation, influencing the control of translation initiation, the elongation speed, and the mRNA translation selectivity. This is due to the presence of subpopulations of the ribosomes, which differ in rRNAs and protein composition, their modifications and protein stoichiometry. In this publication, we focused our attention on the ribosomal heterogeneity in eukaryotes, which results from the changes in the stoichiometry of the ribosomal proteins and the existence of protein paralogs.

DOI: https://doi.org/10.18388/pb.2021_467

mSystems. 2023 Jan 18. e0109822

Inhibition of Ribosome Assembly and Ribosome Translation Has Distinctly Different Effects on Abundance and Paralogue Composition of Ribosomal Protein mRNAs in Saccharomyces cerevisiae.

Md Shamsuzzaman, Nusrat Rahman, Brian Gregory, Ananth Bommakanti, Janice M Zengel, Vincent M Bruno, Lasse Lindahl.

Many mutations in genes for ribosomal proteins (r-proteins) and assembly factors cause cell stress and altered cell fate, resulting in congenital diseases collectively called ribosomopathies. Even though all such mutations depress the cell's protein synthesis capacity, they generate many different phenotypes, suggesting that the diseases are not due simply to insufficient protein synthesis capacity. To learn more, we investigated how the global transcriptome in Saccharomyces cerevisiae responds to reduced protein synthesis generated in two different ways: abolishing the assembly of new ribosomes and inhibiting ribosomal function. Our results showed that the mechanism by which protein synthesis is obstructed affects the ribosomal protein transcriptome differentially: ribosomal protein mRNA abundance increases during the abolition of ribosome formation but decreases during the inhibition of ribosome function. Interestingly, the ratio between mRNAs from some, but not all, pairs of paralogous ribosomal protein genes encoding slightly different versions of a given r-protein changed differently during the two types of stress, suggesting that expression of specific ribosomal protein paralogous mRNAs may contribute to the stress response. Unexpectedly, the abundance of transcripts for ribosome assembly factors and translation factors remained relatively unaffected by the stresses. On the other hand, the state of the translation apparatus did affect cell physiology: mRNA levels for some other proteins not directly related to the translation apparatus also changed differentially, though not coordinately with the r-protein genes, in response to the stresses. IMPORTANCE Mutations in genes for ribosomal proteins or assembly factors cause a variety of diseases called ribosomopathies. These diseases are typically ascribed to a reduction in the cell's capacity for protein synthesis. Paradoxically, ribosomal mutations result in a wide variety of disease phenotypes, even though they all reduce protein synthesis. Here, we show that the transcriptome changes differently depending on how the protein synthesis capacity is reduced. Most strikingly, inhibiting ribosome formation and ribosome function had opposite effects on the abundance of mRNA for ribosomal proteins, while genes for ribosome translation and assembly factors showed no systematic responses. Thus, the process by which the protein synthesis capacity is reduced contributes decisively to global mRNA composition. This emphasis on process is a new concept in understanding ribosomopathies and other stress responses.

Keywords: cell stress; nucleolar stress; ribosomal protein paralogues; ribosomal proteins; ribosome biogenesis; transcriptome; translation; translation stress

DOI: https://doi.org/10.1128/msystems.01098-22

Semin Cell Dev Biol. 2023 Jan 13. pii: S1084-9521(23)00003-4. [Epub ahead of print]

Emerging implications for ribosomes in proximity to mitochondria.

Bar Cohen, Adi Golani-Armon, Yoav S Arava.

Synthesis of all proteins in eukaryotic cells, apart from a few organellar proteins, is done by cytosolic ribosomes. Many of these ribosomes are localized in the vicinity of the functional site of their encoded protein, enabling local protein synthesis. Studies in various organisms and tissues revealed that such locally translating ribosomes are also present near mitochondria. Here, we provide a brief summary of evidence for localized translation near mitochondria, then present data suggesting that these localized ribosomes may enable local translational regulatory processes in response to mitochondria needs. Finally, we describe the involvement of such localized ribosomes in the quality control of protein synthesis and mitochondria. These emerging views suggest that ribosomes localized near mitochondria are a hub for a variety of activities with diverse implications on mitochondria physiology.

Keywords: Localized translation; MitoRQC; Mitochondria; RNA binding proteins; Ribosomal quality control; Ribosomes; Translation regulation; mRNA localization

DOI: https://doi.org/10.1016/j.semcdb.2023.01.003

Nat Commun. 2023 Jan 18. 14(1): 300

Kaposi's sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs.

James C Murphy, Elena M Harrington, Sophie Schumann, Elton J R Vasconcelos, Timothy J Mottram, Katherine L Harper, Julie L Aspden, Adrian Whitehouse.

Historically, ribosomes were viewed as unchanged homogeneous macromolecular machines with no regulatory capacity for mRNA translation. An emerging concept is that heterogeneity of ribosomal composition exists, exerting a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct specialised ribosomes that actively regulate mRNA translation. Viruses lack their own translational machinery and impose high translational demands on the host during replication. We explore the possibility that KSHV manipulates ribosome biogenesis producing specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic replication. We demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and the KSHV ORF11 protein, with small ribosomal subunit precursor complexes during lytic replication. BUD23 depletion resulted in significantly reduced viral gene expression, culminating in dramatic reduction of infectious virion production. Ribosome profiling demonstrated BUD23 is essential for reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the downstream coding sequence. Results provide mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes facilitating efficient translation of viral mRNAs.

DOI: https://doi.org/10.1038/s41467-023-35914-5

Nucleic Acids Res. 2023 Jan 20. pii: gkac1273. [Epub ahead of print]

Rare ribosomal RNA sequences from archaea stabilize the bacterial ribosome.

Amos J Nissley, Petar I Penev, Zoe L Watson, Jillian F Banfield, Jamie H D Cate.

The ribosome serves as the universally conserved translator of the genetic code into proteins and supports life across diverse temperatures ranging from below freezing to above 120°C. Ribosomes are capable of functioning across this wide range of temperatures even though the catalytic site for peptide bond formation, the peptidyl transferase center, is nearly universally conserved. Here we find that Thermoproteota, a phylum of thermophilic Archaea, substitute cytidine for uridine at large subunit rRNA positions 2554 and 2555 (Escherichia coli numbering) in the A loop, immediately adjacent to the binding site for the 3'-end of A-site tRNA. We show by cryo-EM that E. coli ribosomes with uridine to cytidine mutations at these positions retain the proper fold and post-transcriptional modification of the A loop. Additionally, these mutations do not affect cellular growth, protect the large ribosomal subunit from thermal denaturation, and increase the mutational robustness of nucleotides in the peptidyl transferase center. This work identifies sequence variation across archaeal ribosomes in the peptidyl transferase center that likely confers stabilization of the ribosome at high temperatures and develops a stable mutant bacterial ribosome that can act as a scaffold for future ribosome engineering efforts.

DOI: https://doi.org/10.1093/nar/gkac1273

Mol Cell. 2023 Jan 13. pii: S1097-2765(22)01213-8. [Epub ahead of print]

De-centralizing the Central Dogma: mRNA translation in space and time.

Ashley M Bourke, Andre Schwarz, Erin M Schuman.

As our understanding of the cell interior has grown, we have come to appreciate that most cellular operations are localized, that is, they occur at discrete and identifiable locations or domains. These cellular domains contain enzymes, machines, and other components necessary to carry out and regulate these localized operations. Here, we review these features of one such operation: the localization and translation of mRNAs within subcellular compartments observed across cell types and organisms. We describe the conceptual advantages and the "ingredients" and mechanisms of local translation. We focus on the nature and features of localized mRNAs, how they travel and get localized, and how this process is regulated. We also evaluate our current understanding of protein synthesis machines (ribosomes) and their cadre of regulatory elements, that is, the translation factors.

Keywords: local translation; mRNA localization; protein synthesis; ribosome; translation factor

DOI: https://doi.org/10.1016/j.molcel.2022.12.030