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Review
, 23 (2), 324-34

RNA Granules: The Good, the Bad and the Ugly

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Review

RNA Granules: The Good, the Bad and the Ugly

María Gabriela Thomas et al. Cell Signal.

Abstract

Processing bodies (PBs) and Stress Granules (SGs) are the founding members of a new class of RNA granules, known as mRNA silencing foci, as they harbour transcripts circumstantially excluded from the translationally active pool. PBs and SGs are able to release mRNAs thus allowing their translation. PBs are constitutive, but respond to stimuli that affect mRNA translation and decay, whereas SGs are specifically induced upon cellular stress, which triggers a global translational silencing by several pathways, including phosphorylation of the key translation initiation factor eIF2alpha, and tRNA cleavage among others. PBs and SGs with different compositions may coexist in a single cell. These macromolecular aggregates are highly conserved through evolution, from unicellular organisms to vertebrate neurons. Their dynamics is regulated by several signaling pathways, and depends on microfilaments and microtubules, and the cognate molecular motors myosin, dynein, and kinesin. SGs share features with aggresomes and related aggregates of unfolded proteins frequently present in neurodegenerative diseases, and may play a role in the pathology. Virus infections may induce or impair SG formation. Besides being important for mRNA regulation upon stress, SGs modulate the signaling balancing apoptosis and cell survival. Finally, the formation of Nuclear Stress Bodies (nSBs), which share components with SGs, and the assembly of additional cytosolic aggregates containing RNA -the UV granules and the Ire1 foci-, all of them induced by specific cell damage factors, contribute to cell survival.

Figures

Figure 1
Figure 1. PBs, SGs and related RNA granules in trypanosomes, flies and mammals
A and B, PBs are heterogenous. A. Immunofluorescence for DCP1a; Ge-1/Hedls and Pacman/XRN1 in Drosophila Schneider S2R+ cells. Double-stained foci are frequent in the case of DCP1a and Ge-1, and infrequent for DCP1a and Pacman. In all cases, single-stained foci are highly frequent. Bars: 1 µm. B. The P-body components DCP1a and rck/p54 form separate foci in hippocampal neurons, and a fraction of them partially overlap The dendritic cytoskeleton is stained in blue (kindly provided by Luciana Luchelli, Instituto Leloir, see also [56]). Bars: 1 µm. C, ER-stress induces the transient formation of SGs (red) in mammalian cells. In a fraction of cells SGs last longer than 8 hs and fuse with PBs (green) (See also [16]). Bars: 5 µm. D. Polyadenylated RNA granules are induced in T. cruzi cells exposed to nutritional stress. Left, polyA granules contain the exoribonuclease XRNa (kindly provided by Alejandro Casola and Carlos Frasch, Universidad Nacional de San Martín, Argentina). Right, polyA granules are distinct from tRNA granules, which contain 5’halves of tRNA molecules cleaved upon stress (kindly provided by A. Cayota, Institut Pasteur de Montevideo, Montevideo, Uruguay). Bars: 1 µm.
Figure 2
Figure 2
Comparative time-course of SG formation, elF2alpha phosphorylation, protein synthesis, PB induction and heat shock protein expression upon stress induction. Maximal SG formation, elF2alpha phosphorylation and protein synthesis inhibition occur quite simultaneously, between 1–2 h upon oxidative stress in mammalian or insect cells, or around 2–4 h upon ER-stress, respectively [16, 17]. All trough during the response, SG grow, undergo fusion and fission and remodelate. They can incorporate or lose components during the response (see text). Two hours after oxidative stress induction, the foci begin to dissolve synchronously and they completely vanish one hour later. A similar time course, with the time of maximal SG formation at around 2 h and a slower dissolution phase is observed upon ER-stress induction. SG dissolution occurs with similar time-course either in the presence or absence of oxidative or ER-stress inductors, or upon booster applications [16, 17]. SGs are induced rapidly by inhibitors of translation initiation, and do not dissolve unless the drug is removed (Loschi and Boccaccio unpublished). elF2alpha phosphorylation reachs maximal levels and may go back down basal levels during SG dissolution. Protein synthesis shuts off at the time of maximal SG formation and then partially recovers during SG disassembly. This correlates with HSP70 expression, which keeps accumulating beyond SG disassembly. Synthesis of heat shock proteins lasts for several hours, whereas recovery of normal protein synthesis takes a longer time. PBs are induced by cellular stress, then they may return to basal conditions, move to the perinucleus or vanish, and their components can be incorporated to SGs [16, 50, 122]. Paralleling SG formation in the cytoplasm, the formation of nuclear stress bodies (nSB) occurs at specific foci in the nucleus (see text). Like SGs, nSB are transient and remodellate during the response.

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