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The Secret Recipe for RNA Granules

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The Secret Recipe for RNA Granules RESEARCH HIGHLIGHTS Nature Reviews Molecular Cell Biology | AOP, published online 30 May 2012; doi:10.1038/nrm3372 PROTEIN AGGREGATION The secret recipe for RNA granules RNA granules, including stress As the b-isox-induced precipitates In addition, mutational analyses in granules of mammalian cells and were significantly enriched in U2OS2 cells indicated that the Tyr reversible neuronal granules in dendrites, are mRNAs and RBPs that are found in residues of the 27 (Gly/Ser)-Tyr- polymer­ization membrane-free cytoplasmic struc- RNA granules, the authors investi- (Gly/‌Ser) triplet repeats of the tures composed of RNA molecules gated which structural components FUS low-complexity domain were may drive the and RNA-binding proteins (RBPs). of mRNAs and RBPs trigger the required for the inclusion of FUS inclusion and RNA granules have been implicated formation of RNA granule-like in endogenous stress granules. exclusion of in the control of mRNA localiza- b-isox-induced precipitates. Moreover, cell-free experiments RBPs in RNA tion, and, although they were first Interestingly, the RNA granule- suggested that low-complexity observed more than 100 years ago, like structures were enriched domain-containing proteins poly­ granules the mechanism underlying their for mRNAs with extended 3ʹ merize into amyloid-like fibres that formation has been elusive. Here, untranslated region sequences and differ from pathogenic prion-like McKnight and colleagues describe RBP-binding sites. However, ribo- amyloids in that they can be reversibly cell-free RNA granule formation nuclease treatment did not inhibit depolymerized. Such amyloid-like and propose a set of principles that the formation of RNA granule-like fibres could be extended by the addi- may drive the formation of RNA precipitates, suggesting that it is the tion of homotypic and heterotypic granules in vivo. RBP component that may lead to low-complexity-domain-containing The chemical isoxazole has been the formation of such structures. proteins, and this depended on the reported to induce differentiation Computational studies revealed Tyr residues of the low-complexity of stem cells, and the authors that low-complexity polypeptide domains. By contrast, phosphoryla- used a biotinylated derivative sequences (which are often observed tion of this domain at multiple Ser (b-isox) to characterize this in RBPs and DNA-binding pro- residues inhibited further low- function. However, the obser- teins) are frequent within both complexit­y domain-dependent vation that the addition of RNA granule RBP constituents protein polymerization. Thus, this b-isox to cell lysates resulted and b-isox‑precipitated proteins. reversible polymerization may drive in the formation of protein- Moreover, low-complexity domains the inclusion and exclusion of RBPs in and mRNA-containing (and not domains involved in RNA granules in a manner that can be precipitates shifted the RNA binding) were required for regulated by local RBP concentration focus of the authors. b-isox-induced precipitation. and post-translational modification­s Analysis of the X-ray structure of such as phosphorylation. b-isox microcrystals led the authors Together, these findings reveal the to suggest that their wavy surface previously unappreciated role of low- enables the reversible organization of complexity polypeptide sequences low-complexity domains, which are in the formation of membrane-free disordered in soluble proteins, into subcellular structures such as RNA an extended β-strand. So, such a granules. The authors speculate that transition in the organization locally controlled formation of such of low-complexity domains structures may underlie many cellu- may also occur in vivo. lar functions, including RNA splicing Strikingly, the presence of and gene transcription. a low-complexity domain in Maria Papatriantafyllou the stress granule constituent ORIGINAL RESEARCH PAPERS Kato, M. et al. FUS (fused in sarcoma) was Cell-free formation of RNA granules: low essential and sufficient for the complexity sequence domains form dynamic fibers with hydrogels. Cell 149, 753–767 (2012) | cell-free formation of RNA Han, T. W. et al. Cell-free formation of RNA granule-like protein hydrogels granules: bound RNAs identify features and at high protein concentrations components of cellular assemblies. Cell 149, 768–779 (2012) even in the absence of b-isox. Vicky Summersby/NPG NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 13 | JULY 2012 © 2012 Macmillan Publishers Limited. All rights reserved.
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