Improved activities of CBP, hnRNPs and proteasome following down regulation of noncoding hsrω transcripts help suppress polyQ pathogenesis in fly models

Abstract

Following earlier reports on modulation of polyQ toxicity in Drosophila by the developmentally active and stress-inducible noncoding hsrω gene, we investigated possible mediators of this modulation. RNAi-mediated down regulation of the large nuclear hsrω-n transcript, which organizes the nucleoplasmic omega speckles, suppressed the enhancement of polyQ toxicity brought about by reduced availability of the hnRNP Hrb87F or of the transcriptional regulator, CREB Binding Protein (CBP). Levels of CBP RNA and protein were reciprocally affected by hsrω transcript levels in eye disc cells. Our data suggest that CBP and hnRNPs like Hrb57A and Hrb87F physically interact with each other. In addition, down regulation of hsrω transcripts partially rescued eye damage following compromised proteasome activity, while over-expression of hsrω and/or polyQ proteins disrupted the proteasomal activity. Rescue of polyQ toxicity by hsrω-RNAi required normal proteasomal function. We suggest that hsrω-RNAi suppresses polyQ toxicity by elevating cellular levels of CBP, by enhancing proteasome-mediated clearance of the pathogenic polyQ aggregates and by inhibiting induced apoptosis. The direct and indirect interactions of the hsrω transcripts with a variety of regulatory proteins like hnRNPs, CBP, proteasome, DIAP1 etc, reinforce the view that the noncoding hsrω RNA functions as a "hub" in cellular networks to maintain homeostasis by regulating the functional availability of crucial cellular regulatory proteins.