Molecular Motors and Staufen Regulate SG Dynamics.

LOSCHI M; THOMAS, MG; DESBATS, MA; MARTINEZ TOSAR LJ; LEISHMAN C; BOCCACCIO GL

Ashville, USA

Congreso; RNA Turnover 2008. RNA Regulatory Mechanisms implicated in human diseases both rare and common; 2008

The formation of cytoplasmic aggregates known as stress granules (SGs) harbouring abortive translation initiation complexes is a conserved hallmark of the stress response. SGs are transient, their assembly depends on the regulated aggregation of specific RNA-binding proteins and their disassembly requires the chaperone hsp70. SGs are in dynamic equilibrium with translating polysomes and their components rapidly shuttle in and out of the foci. Here we investigated the role of the double-stranded RNA-binding protein Staufen 1 and of molecular motors in SG dynamics. We have previously shown that Staufen 1, a double-stranded RNA binding protein normally associated to polysomes, is recruited to SGs (Thomas et al., MBC 2005; Baez and Boccaccio JBC, 2005). Here we show that Staufen 1 stabilizes polysomes against stress, thus impairing SG formation. We have also analyzed the role of anterograde and retrograde motors in SG formation. We found that impairment of retrograde transport by disruption of the minus-end directed motor dynein or of specific adaptor molecules inhibits SG formation. Conversely, impairment of anterograde transport by disruption of the plus-end directed motor kinesin delays SG dissolution. The requirement of dynein and kinesin for aggregation and subsequent disassembly of SGs is conserved in mammalian and Drosophila cells. We found that inhibition of SG formation by disruption of motor activity does not affect the stress-induced translational silencing. We propose that SG formation is a two step-process. First, stress stimulus provokes initiation blockage thus triggering polysome disassembly in a Satufen 1-dependent manner. Then, aggregation of abortive translation initiation complexes is mediated by dynein-dependent retrograde movement. Thereafter, SG disassembly requires kinesin-dependent transport of released components.