Translationally Silenced mRNAs Are Sequestered in a Variety of RNA Granules
 

KEY CONCEPTS
-RNA granules are formed by aggregation of translationally silenced mRNA and many different proteins.
- Germ cell granules and neuronal granules function in translational repression and transport.
- Processing bodies (PBs) containing mRNA decay components are present in most or all cells.
- Stress granules (SGs) accumulate in response to stressinduced inhibition of translation.
The occurrence in germ cells and neurons of macroscopic, cytoplasmic particles containing mRNA has been known for many years. RNA granules were considered to be mRNA storage structures unique to these specialized cell types. Recent studies have vastly expanded the known occurrence and probable roles of these and related granules. One similarity among all of the known RNA granules is that they harbor untranslated mRNAs and about 50 to 100 different proteins, depending on granule type. The protein components differ among granule types, though all granules contain sets of proteins that mediate aggregation through self-interaction motifs. RNA granules form by aggregation of mRNPs and protein and are heterogeneous in size. The cytoskeleton and motor proteins also can play roles in assembly and disassembly of granules (as well as their transport).
Germ cell granules (also called maternal mRNA granules) are found in oocytes from a variety of organisms. These granules comprise collections of mRNAs that are held in a state of translational repression until they are activated during subsequent development. Repression is achieved by extensive deadenylation, and activation is achieved by polyadenylation. These granules also may carry mRNAs being transported to specific regions of this large cell .
Neuronal granules are similar to maternal mRNA granules in that they function in the translational repression and transport of specific mRNAs. These granules are essential for normal neuronal function. New studies suggest that at least some mRNA degradation occurs within discrete particles throughout the cytoplasm of most or all cell types. These particles, called processing bodies (PBs), are the only granule type that contains proteins involved in mRNA decay, including the decapping machinery and Xrn1 exonuclease. mRNAs silenced via RNAi and miRNA pathways are present in PBs. PABPs are not found in PBs, suggesting that deadenylation precedes mRNA localization into these structures. Processing bodies are dynamic, increasing and decreasing in size and number, and even disappearing, under different cellular and experimental conditions that affect translation and decay. For example, release of mRNAs from polysomes by a drug that inhibits translation initiation results in a large increase in PB number and size, as does slowing degradation by partial inactivation of decay components. Not all resident mRNAs are doomed for destruction, though; some can be released for translation, but which ones and why they are freed is not yet clear. It is not known whether all mRNA degradation normally occurs in these bodies, or even what function(s) they serve. One idea is that concentrating powerful destructive enzymes in isolated locations renders mRNA degradation more safe and efficient. Another is that they serve as temporary storage sites when the capacity of the decay and/or translation machinery is exceeded.
Another mRNA-containing particle related to PBs is called a stress granule (SG). Whereas PBs are constitutive, SGs only accumulate in response to stress-induced inhibition of translation initiation (a response common to probably all eukaryotic organisms). PBs and SGs share some, but not all, protein components. For example, SGs lack components of the RNA decay machinery, which PBs have, but include many translational initiation components that PBs lack. Both types of particle can coexist in one cell, and the size and numbers of both increase under stress conditions. mRNAs may be exchanged between the two types of particles. In the presence of polysome-stabilizing drugs, which trap mRNAs in a static state of translation, both PBs and SGs become smaller or disappear, suggesting that the granule mRNAs are normally in a dynamic equilibrium with the population of mRNAs being translated. SGs share many components with neuronal granules. Of particular interest is the fact that a number of shared RNA-binding proteins, known to be essential to SG formation, have been implicated in neuronal defects.