NOVEL STRESS GRANULE REGULATORS IDENTIFIED IN AN RNAI SCREEN IN Drosophila

PÉREZ-PEPE M ; LOSCHI M; ARÁN M; THOMAS MG; WOLOSIUK R; COOKE A; HENZTE M; BOCCACCIO GL

Congreso; - SAIB - 51 Annual Meeting Argentine Society for Biochemistry and Molecular Biology; 2015

Stress granules (SGs) are cytoplasmic accretions that form transiently in all cell types undergoing acute stress. SGs contain polyadenylated mRNA, a number of translation factors and several RNA-binding proteins. Their significance to cell survival remains elusive. SG assembly and disassembly is a multi-step process that depends on I) Translation initiation blockage and destabilization of polysomes II) Retrograde transport by dynein and adaptor proteins III) Aggregation through specific proteins IV) Dissolution and dispersion mediated by stress-induced chaperones and kinesin. We performed an RNAi?based screen in Drosophila to identify signaling pathways that regulate SG dynamics. We identified 32 positive and 15 negative modulators of SG formation. As expected, eIF2α kinases facilitate SG assembly whereas the antagonistic phosphatase PP1α helps SG dissolution. Several hits are related to mRNA metabolism and translation, cytoskeleton organization and intracellular transport, and a number are linked to neurodegenerative diseases. We are currently investigating these novel SG regulatory mechanisms in the Drosophila brain. In addition, we are investigating how 2-Cys Peroxiredoxins, which are peroxidases and RNA binders with stress-regulated chaperone activity, regulate SG formation.