Improved activities of CREB binding protein, heterogeneous nuclear ribonucleoproteins and proteasome following downregulation of noncoding hsrω transcripts help suppress poly(Q) pathogenesis in fly models

Abstract

Following earlier reports on modulation of poly(Q) toxicity in Drosophila by the developmentally active and stress-inducible noncoding hsrω gene, we investigated possible mediators of this modulation. RNAi-mediated downregulation of the large nuclear hsrω-n transcript, which organizes the nucleoplasmic omega speckles, suppressed the enhancement of poly(Q) toxicity brought about by reduced availability of the heterogeneous nuclear ribonucleoprotein (hnRNP) Hrb87F and of the transcriptional regulator, cAMP response element binding (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, downregulation of hsrω transcripts partially rescued eye damage following compromised proteasome activity, while overexpression of hsrω and/or poly(Q) proteins disrupted the proteasomal activity. Rescue of poly(Q) toxicity by hsrω-RNAi required normal proteasomal function. We suggest that hsrω-RNAi suppresses poly(Q) toxicity by elevating cellular levels of CBP, by enhancing proteasome-mediated clearance of the pathogenic poly(Q) 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, Drosophila inhibitor of apoptosis protein 1 (DIAP1), etc., reinforce the view that the noncoding hsrω RNA functions as a "hub" in cellular networks to maintain homeostasis by coordinating the functional availability of crucial cellular regulatory proteins. Copyright © 2010 by the Genetics Society of America.