Dynamic conversion of cytoplasmic RNA granules into stress granules.

M. GABRIELA THOMAS;; LEANDRO J. MARTINEZ TOSAR;; M. VERÓNICA BAEZ;; MARIELA LOSCHI;; M. ANDREA DESBATS;; CLAUDIA C. LEISHMAN; GRACIELA L. BOCCACCIO

Banff, Alberta, Canada,

Congreso; RNA 2005, Tenth Annual Meeting of the RNA Society,; 2005

Cytoplasmic RNA granules packing mRNAs occur throughout evolution from insect oocytes to mammalian oligodendrocytes and neurons. FMRP, Staufen, SMN, Smaug and other RNA binding proteins (RBPs) are conserved components of RNA granules. We found different RBPs residing in distinct RNA granule populations, likely containing particular sets of mRNAs that are controlled coordinately with respect to their subcellular localization, activation or decay. When exposed to stress conditions, eukaryotic cells are able to build up a different kind of RNA-protein aggregates of larger size, known as stress granules (SGs), that transiently harbor mRNAs silenced during the stress response. TIA1 and TIAR, which are normally restricted the nucleus, concentrate in these structures, that are different from GW182 positive-degradation foci. We found that both cap binding proteins eIF4E and CBP80, the latter being associated to mRNAs in their pioneer translation rounds, are present in SGs. RNA granules containing ribosomes and SMN, FMRP, Staufen or Smaug are plastic, they depend on the cellular translational activity and are converted into SGs upon different stressors. Normal RNA granules are remodeled during SG formation, as they include large ribosomal subunits and exclude TIA1 and TIAR. In addition, intracellular repositioning occurs, the disperse distribution of normal granules turning into a more perinuclear localization in SGs. Both microtubules and microfilaments are involved, as disruption of these cytoskeleton structures impairs SG assembly. Kinetic analysis shows a stereotypical time course of SG formation characterized by a sequential recruitment of RBPs. Downregulation of component RBPs by siRNA inhibits SG formation. It remains to be determined which are the signal transduction pathways regulating the conversion of normal RNA granules into stress granules; what are the cellular mechanisms controlling the retrograde transport of RNPs, and how is the normal distribution of mRNPs recovered after relief of the stress conditions.