Ribosomopathies: There’s strength in numbers

BACKGROUND Ribosomopathies are a heterogeneous group of human disorders that are in some cases known, and in other cases suspected, to result from ribosome dysfunction. This group broadly comprises two categories: (i) disorders caused by single-copy mutations in specific ribosomal proteins, and (ii) disorders associated with defects in ribosome biogenesis factors. The phenotypic patterns among different ribosomopathies in both categories are divergent but do tend to share some overlapping features. These include effects on bone marrow–derived cell lineages and skeletal tissues. These common tissue specificities of the different ribosomopathies are challenging to reconcile with the ubiquitous requirement for ribosomes in all cells. ADVANCES Several models have been advanced to explain how the dysfunction of the protein synthesis machinery is so variably expressed at the phenotypic level. An increasing number of studies in models of distinct ribosomopathies have revealed that “ribosomal stress” signals converge on the p53 signaling pathway in affected cells and tissues. In these models, a key consequence of ribosome dysfunction is cell- and tissue type–restricted activation of p53-dependent cell cycle arrest and apoptosis. However, the specific translational events upstream of p53 activation that lead to some cells being affected, with others being spared, are unknown. We review evidence relating to two hypotheses that have been proposed to explain such tissue-specific effects of ribosome dysfunction. One hypothesis is that ribosome dysfunction (or deficiency) can affect global and messenger RNA (mRNA)–specific translational control, and that certain specific cells or tissues may be more vulnerable to ribosome dysfunction. A critical feature of this view is that mRNAs are variably dependent on cellular ribosome concentration, with more poorly initiated mRNAs being typically more sensitive to perturbations in ribosome concentration or function. Several recent studies suggest that the sensitivities of certain tissues to ribosomopathies, including reticuloctyes and platelets, may be related to differences in core processes of translation in these cells related to ribosome recycling and rescue. Perturbations in these processes will have a great impact on ribosome homeostasis and thus on broad aspects of gene expression. Related studies in the brain have revealed disease phenotypes in genetic backgrounds with deficiencies in ribosome rescue and in a specific neuronal transfer RNA. Together, these molecular insights provide a new perspective on ribosomopathies and their tissue specificities, while also raising a number of important questions to pursue. The other hypothesis is that ribosomes from different tissues may have different compositions of core or more loosely associated proteins and posttranslational modifications, and that this heterogeneity could be critical to the translation of specific mRNAs. This is referred to as the “specialized” ribosome hypothesis. We argue that while such heterogeneity in ribosome composition likely exists in different tissues, such complex explanations may not be needed to explain the differences in gene expression that result from losses of specific ribosomal proteins. It is simpler to hypothesize that differences in mRNA-specific rates of initiation and changes in ribosome concentration can adequately explain much (if not all) of the diversity of gene expression changes in different tissues as a result of ribosomal mutations. OUTLOOK A cohesive mechanistic model connecting dysfunction of the ribosome to the specific phenotypic consequences observed in ribosomopathies remains a challenging goal. For example, it is inherently difficult to assess the function of particular ribosomes in a cell, and thus to differentiate among various models to explain the impacts of ribosome deficiencies on gene expression. Further biochemical analyses of the fundamental processes underlying the cellular response to protein synthesis dysfunction, refinements in cellular and animal models of ribosomopathies, and greater dialogue between clinical and basic scientists will all be important to extend our current understanding.