RNA assemblages orchestrate complex cellular processes - PubMed (original) (raw)
Review
RNA assemblages orchestrate complex cellular processes
Finn Cilius Nielsen et al. Bioessays. 2016 Jul.
Abstract
Eukaryotic mRNAs are monocistronic, and therefore mechanisms exist that coordinate the synthesis of multiprotein complexes in order to obtain proper stoichiometry at the appropriate intracellular locations. RNA-binding proteins containing low-complexity sequences are prone to generate liquid droplets via liquid-liquid phase separation, and in this way create cytoplasmic assemblages of functionally related mRNAs. In a recent iCLIP study, we showed that the Drosophila RNA-binding protein Imp, which exhibits a C-terminal low-complexity sequence, increases the formation of F-actin by binding to 3' untranslated regions of mRNAs encoding components participating in F-actin biogenesis. We hypothesize that phase transition is a mechanism the cell employs to increase the local mRNA concentration considerably, and in this way synchronize protein production in cytoplasmic territories, as discussed in the present review.
Keywords: RNA assemblage; RNA-binding protein; RNP granule; liquid droplet; low-complexity sequence; post-transcriptional RNA regulon.
2016 The Authors BioEssays Published by WILEY Periodicals, Inc.
Figures
Figure 1
Liquid‐liquid phase separation of RNPs and decreased reversibility. At a critical concentration, monomeric RNPs are partitioned into reversible liquid droplets in a heterotypical manner, illustrated by different colors of low‐complexity RBPs. The presence of RNA (drawn as “snakes”) together with dynamic, multiple weak interactions between intrinsically disordered protein regions (not shown), seems critical for droplet formation. In hydrogels, the interactions between the disordered regions are less dynamic because of cross‐β conformations, and hydrogels appear to exhibit a broad spectrum of reversibility. Formation of amyloid‐like inclusions of low reversibility, associated with disease mutations, is shown at the right. Partitioning of RNPs into droplets/hydrogels increases their local concentration by orders of magnitude 38 and thereby the likelihood of fibrillization.
Figure 2
Schematic representation of Drosophila Imp and human IMP1. Numbers refer to amino acid positions bordering various domains. Human IMP1 is composed of 579 amino acids and exhibits six characteristic RNA‐binding modules, namely two N‐terminal RNA recognition motifs (RRM1 and 2), and four C‐terminal hnRNPK homology domains (KH1–4). Whereas two RRMs or four KH domains can be found in other RBPs, the 2 + 4 modular architecture seen in vertebrate IMPs is unique. From both a phylogenetic and experimental standpoint, the four KH domains constitute a functional entity in terms of high‐affinity RNA‐binding, granular RNP assembly, and RNA localization 77. Although Drosophila Imp exhibits rudimentary features of RRMs in minor isoforms, the major isoform of 566 amino acid lacks RRMs. Instead, Drosophila Imp contains a large C‐terminal low‐complexity glutamine‐rich sequence (LCS).
Figure 3
A: Drosophila Imp in cytoplasmic RNP granules. The picture shows a Drosophila S2 cell stained with DAPI (green), anti‐Imp antibody (blue) and phalloidin (red) (all in pseudo‐colors). Imp granules are about 100–200 nm large and located in the perinuclear region and close to the actin mesh. B: Transcripts associated with the Imp‐mediated RNA assemblage. Forty out of the 86 transcripts, identified by three different high‐throughput analyses, participate in growth cone dynamics 64. C: Key proteins involved in the formation and maintenance of F‐actin in lamellipodia. Several effector proteins are needed to nucleate, elongate, depolymerize, bundle and contract the actin filaments in order to reorganize the shape of the leading edge of a cell in response to external guidance cues. Profilin is responsible for the addition of actin monomers to the barbed end of growing filaments by interacting with the barbed‐end protector proteins, the formins and Ena/VASP 78. Formins and Ena/VASP also ensure continuous growth of the filament by inhibiting the binding of capping proteins, Cap2 and Esp8, otherwise capable of blocking the addition of actin monomers 79, 80. In lamellipodia, the mesh‐like form of F‐actin is accomplished by the dendritic nucleator proteins, the Arp2/3 complex, functioning as branch point holders, where they nucleate new filaments that branch off from pre‐existing ones 78. The recycling of actin subunits and actin remodelling is vital for movement of the cell. Cofilin in its unphosphorylated form binds to and twists the actin filament toward the pointed end, and the severing creates additional barbed ends, enhancing the turnover of actin subunits 81.
Figure 4
Schematic representation of the role of RNP granules/droplets in the segregation of mRNA assemblages. In the nucleus, transcripts are associated with particular RBPs, that – via low‐complexity sequences – drive the formation of liquid droplets containing mRNAs encoding factors participating in a particular biological process or macromolecular complex. Following cellular trafficking to the final destination, the increase in local mRNA concentration facilitates synchronous on‐site protein production.
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