Novel Stress Granule regulators identified in an RNAi screen in Drosophila

PEREZ PEPE, M; LOSCHI M; ARAN, M; THOMAS MG; WOLOKZIUK, R; COOKE, A; HENTZE, M; BOCCACCIO GL

Mar del Plata

Congreso; SAIB (Sociedad Argentina de Investigaciones Bioquímicas y Biología Molecular) 2015; 2015

SAIB (Sociedad Argentina de Investigaciones Bioquímicas y Biología Molecular)

Stressgranules (SGs) are cytoplasmic accretions that form transiently in all celltypes undergoing acute stress. SGs contain polyadenylated mRNA, a number oftranslation factors and several RNA-binding proteins. Their significance tocell survival remains elusive. SGassembly and disassembly is a multi-step process that depends on I) Translationinitiation blockage and destabilization of polysomes II) Retrograde transportby dynein and adaptor proteins III) Aggregation through specific proteins IV)Dissolution and dispersion mediated by stress-induced chaperones andkinesin.  We performed an RNAi ?based  screen in Drosophilato identify signaling pathways that regulate SG dynamics. We identified 32positive and 15 negative modulators of SG formation. As expected, eIF2á kinases facilitate SG assembly whereasthe antagonistic phosphatase PP1áhelps SG dissolution. Several hits are related to mRNA metabolism andtranslation, cytoskeleton organization and intracellular transport, and anumber are linked to neurodegenerative diseases. We are currentlyinvestigating these novel SG regulatory mechanisms in the Drosophila brain. In addition, we are investigating how 2-CysPeroxiredoxins, which are peroxidases and RNA binders with stress-regulatedchaperone activity, regulate SG formation. We thank the DRSC, Harvard MedicalSchool, and ANPCyT, CONICET and UBA, Argentina for funding.