The Promises and pitfalls of specialized ribosomes

Where Functional Ribosome Heterogeneity Could Exist

While there is ample evidence for ribosome heterogeneity (Ferretti and Karbstein, 2019; Genuth and Barna, 2018), the lack of functional data to support specific roles for most ribosome subpopulations is one of the reasons the topic remains controversial. In addition, there are also conceptual problems with the proposal of different ribosome populations modulating gene expression. First, cells go to great lengths to ensure the uniform composition and functional integrity of the ribosome (Huang et al., 2020; Parker et al., 2019), exactly the opposite of what the concept suggests. Moreover, ribosomes lacking individual ribosomal proteins (RPs), or rRNA modifications are associated with a number of different diseases (Amsterdam et al., 2004; Armistead et al., 2009; Babaian et al., 2020; Guimaraes and Zavolan, 2016; Kulkarni et al., 2017). Together, these considerations suggest that ribosome heterogeneity has dangerous negative consequences that cells carefully avoid. Second, two (or more) ribosome populations with different elongation speeds, or propensities to slow at different sequences, will lead to ribosome collisions as the faster type catches up with the slower one (Simms et al., 2017). These collisions result in decay of the bound mRNA (Simms et al., 2017) and the offending ribosome (Cole et al., 2009), thus purifying the cell of the heterogeneity. Third, implicit in the proposal of ribosome heterogeneity contributing to regulated gene expression is the idea that ribosome populations change. However, ribosomes are exceedingly stable (LaRiviere et al., 2006) and turned over only via cell division. Moreover, ribosome assembly is very energetically costly (Warner, 1999) and turned off under any stress (Gasch et al., 2000) - the exact condition when one would want to change gene expression.

These considerations do not mean that heterogeneous ribosomes do not play functional roles in physiological processes. Instead, they suggest that functional heterogeneity is likely limited to certain circumstances, where the above considerations no longer hold. For example, cell type-specific ribosomes could contribute to cell type-specific translational profiles, although in that case each cell type has a homogeneous ribosome population. Also, during development rapid cellular division and the resulting requirement for massive ribosome synthesis could lead to a (relatively) rapid change in ribosome populations. If these are distributed asymmetrically during cell division, this could further lead to rapid separation of the two ribosome pools. Ribosome populations could also change rapidly and reversibly via reversible posttranslational modifications (Mazumder et al., 2003), or via reversible release of RPs, as we have recently shown for Rps26 (Yang and Karbstein, 2022). Both mechanisms also allow for regulation, important in avoiding overproduction of RP-deficient ribosomes with pathogenic potential. Ribosome collisions can be avoided if two ribosome populations have selectivity for different mRNAs during initiation, e.g. by contributing to Kozak sequence recognition, as we have shown for Rps26 (Ferretti et al., 2017), or by binding uncapped viral mRNAs. Moreover, cellular localization of mRNAs and ribosomes might also contribute to demixing of ribosome populations. Ribosomes that are defective in the response to collisions could also escape their purifying selection. Because the interface of the collided ribosomes involves specific RP-dependent contacts, it is likely that ribosomes lacking those RPs would be defective in responding to collisions, as shown for Asc1-deficient yeast (Wang et al., 2018). Finally, if heterogeneity is combined with reduced ribosome numbers, collisions might also be avoided, especially if combined with defects in collision clearance. These examples suggest that while ribosome heterogeneity is problematic for cells, and dealt with swiftly, there are niches where alternative ribosomes might contribute to regulated gene expression.