The ribosome filter hypothesis

Abstract

A variety of posttranscriptional mechanisms affects the processing, subcellular localization, and translation of messenger RNAs (mRNAs). Translational control appears to occur primarily at the initiation rather than the elongation stage. It has been suggested that translation is mediated largely by means of a cap-binding/scanning mechanism. On the basis of recent findings, we propose here that differential binding of particular mRNAs to eukaryotic 40S ribosomal subunits before translation may also selectively affect rates of polypeptide chain production. In this view, ribosomal subunits themselves are considered to be regulatory elements or filters that mediate interactions between particular mRNAs and components of the translation machinery. Differences in these interactions affect how efficiently individual mRNAs compete for ribosomal subunits. These competitive interactions would depend in part on the complementarity between sequences in mRNA and rRNA, as well as on structural differences among ribosomes in different cell types. By these means, translation may either be enhanced through increased recruitment of ribosomes or inhibited through strong interactions that sequester mRNAs. We propose that ribosomal filters may be important in cell differentiation and describe experimental tests for the filter hypothesis.

Fig 1.

mRNA–40S ribosomal subunit interactions and their effects on translation initiation as predicted by the ribosome filter hypothesis. (A) A 40S ribosomal subunit binds to the mRNA at binding sites, which are indicated schematically as gray bars. A subset of such binding sites may function as IRES modules. (B) In some cases, strong interactions between 40S subunits and mRNA binding sites may slow or prevent subsequent movement of the ribosomal subunit and block translation. (C) Weaker interactions between 40S subunits and mRNA binding sites would allow detachment and local clustering, which may favor an initiation event by increasing the local concentration of the 40S subunits. For clarity, only one ribosomal subunit is indicated; local clustering would actually occur as a result of multiple binary interactions. (D) After the initial binding of the 40S subunit to a binding site on the mRNA, the subunit might interact with another region of the mRNA, which may or may not require prior detachment from the initial binding site. The 40S subunit might: 1, move to the cap by means of initiation factors as indicated; 2, reorient on the mRNA and begin scanning; 3, shunt to another binding site; or 4, move to the initiation codon by means of the Met-tRNA_i of the ternary complex (eIF2, GTP, and Met-tRNA_i). Note that the initiation factors indicated in D are not indicated in A–C, but they may also be present during the events depicted. m7G, methylguanosine cap.