Ribosomes take control.

T he ribosome plays a universally conserved role in catalyzing the translation of all mRNAs in every cell across all kingdoms of life. It is therefore not surprising that the ribosome is considered one of the most complex and elaborately formed “molecular machines” in the cell, whose biogenesis is extraordinarily orchestrated, requiring all three RNA polymerases and more than 150 nonribosomal factors (1). Indeed, ribosomes make up much of the cell’s mass, and the eukaryotic ribosome is comprised of four RNA species and 79 ribosomal proteins (RPs). For decades, the dogma has been that, although the ribosome plays a critical function in translating the genomic code, it is largely a “back-stage” participant in gene regulation. This view has been reinforced by the widespread belief, early in the advent of the molecular era, that transcription rather than translation is the major molecular rheostat of gene expression. On the contrary, recent emerging evidence now reveals tremendous variation between expression of the transcriptome and proteome and that the cellular abundance of proteins may be predominantly controlled at the level of translational control (2). By extension, an interesting emerging question is whether the ribosome exerts a previously unappreciated regulatory function or specificity in translational control (3). A PNAS study by Lee et al. contributes to the growing realization of a surprising and emerging role for the ribosome as a “front-stage” participant in gene regulation (4). Moreover, their studies strongly suggest that much can be learned with respect to specialized mechanisms for cellular mRNA translation through the study of viral gene expression. It has long been known that the mysterious lives of viruses may teach us important and critical lessons about mechanisms governing mRNA translation. This is because viral mRNA translational control is exquisite, and viruses often usurp the host translational machinery as an important means for self-propagation (5). One of the most striking mechanisms is the ability of certain viruses to shut down the cellular host general or capdependent translation, allowing for translation of their own viral mRNAs via a cap-independent mechanism. This is achieved through unique cis-acting translational regulatory elements known as internal ribosome entry sites (IRESes) that recruit ribosomes to specific viral mRNAs either directly or through a more limited number of initiation factors (6). Although IRESes were initially identified in viral mRNAs, there has been a subsequent growing appreciation that certain cellular mRNAs also harbor IRES elements in their 5′ UTRs that direct translation initiation, thereby greatly expanding our knowledge of translational regulatory specificity in eukaryotic cells (7). Moreover, it has also been recognized that ribosome-mediated specificity plays an important role in IRES-dependent translation of viral mRNAs. The most notable examples include a role for rRNA modifications (8, 9), as well as a specific requirement for a single RP belonging to the small ribosome subunit, RPS25, in facilitating direct interactions of the ribosome with viral IRES elements (10, 11), thereby promoting a specialized form of translational control. Banking on the knowledge that individual ribosome components may have greater specificity in viral mRNA translation, Lee et al. (4) set out to understand whether certain components of the ribosome may be required for translation of vesicular stomatitis virus (VSV) mRNAs. VSV mRNA translation is very intriguing because, despite the fact that this virus shuts off the host cap-dependent translation machinery, the VSV mRNA itself does not appear to possess an IRES element and requires cap-dependent translation. Moreover, VSV mRNAs are virtually indistinguishable from cellular mRNAs, as they are capped, methylated, and polyadenylated. Thereby, the mechanism that bestows the escape of VSV mRNA translation from shutoff of host translation is an outstanding question. In seeking an answer to this question, Lee et al. (4) carry out an unbiased siRNA screen of RPs in HeLa cells to determine whether specific RPs promote VSV mRNA translation. The results are striking and reveal that a single RP, RPL40, is necessary for VSV mRNA translation, but is largely dispensable for general capdependent protein synthesis, ribosome biogenesis, cell viability, and cell proliferation (Fig. 1). Furthermore, knockdown of RPL40 correlates with a significant decrease in VSV virus output. This effect is remarkably specific to A B