The Discovery of Ribosome Heterogeneity and Its Implications for Gene Regulation and Organismal Life

Abstract

The ribosome has recently transitioned from being viewed as a passive, indiscriminate machine to a more dynamic macromolecular complex with specialized roles in the cell. Here, we discuss the historical milestones from the discovery of the ribosome itself to how this ancient machinery has gained newfound appreciation as a more regulatory participant in the central dogma of gene expression. The first emerging examples of direct changes in ribosome composition at the RNA and protein level, coupled with an increased awareness of the role individual ribosomal components play in the translation of specific mRNAs, is opening a new field of study centered on ribosome-mediated control of gene regulation. In this Perspective, we discuss our current understanding of the known functions for ribosome heterogeneity, including specialized translation of individual transcripts, and its implications for the regulation and expression of key gene regulatory networks. In addition, we suggest what the crucial next steps are to ascertain the extent of ribosome heterogeneity and specialization and its importance for regulation of the proteome within subcellular space, across different cell types, and during multi-cellular organismal development.

Keywords: internal ribosome entry site (IRES); mRNA; mass spectrometry; specialized ribosomes; translation.

Figure 1:. Timeline of key discoveries on ribosome heterogeneity and specialization.

Image of the RNA Tie Club Tie accessed from the Wellcome Library, https://search.wellcomelibrary.org/iii/encore/record/C__Rb1998728.

Figure 2:. Five outstanding questions on the nature of ribosome heterogeneity and its function.

Ribosome heterogeneity can originate from many sources, from initial changes in incorporation of RPs (red) in the nucleus to cytoplasmic exchange of RPs and RAPs (purple) in the cytoplasm to post-translational modifications (such as phosphorylation, P). Each of these different ribosome compositions may be specialized for the translation of specific mRNAs demarcated by unique cis regulons. There additionally may be distinct compositions of ribosomes found in different cell types and in different subcellular locations to optimize the production of proteins necessary in those regions.

Figure 3:. Potential mechanisms underlying disease phenotypes caused by RP haploinsufficiency.

Depletion of an RP may cause tissue dysfunction via multiple direct and indirect effects. If the RP has a specialized function in recruiting particular mRNAs to the ribosome, the translation of those mRNAs may be decreased by the depletion of the RP. Certain RP mutations may also decrease the number of functional ribosomes in the cell, causing global decreases in protein synthesis. Perturbations in ribosome biogenesis can also trigger a stress response mediated by nucleolar stress and p53 activation, which could then have consequences on cellular function and gene expression. Finally, the RP may serve as a docking point for other specialized factors, such as RAPs, which upon RP depletion may no longer be able to associate with the ribosome.