Improved activities of CREB binding protein, heterogeneous nuclear ribonucleoproteins and proteasome following downregulation of noncoding hsromega transcripts help suppress poly(Q) pathogenesis in fly models.
Following earlier reports on modulation of poly(Q) toxicity in Drosophila by the developmentally active and stress-inducible noncoding hsromega gene, we investigated possible mediators of this modulation. RNAi-mediated downregulation of the large nuclear hsromega-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 hsromega 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 hsromega transcripts partially rescued eye damage following compromised proteasome activity, while overexpression of hsromega and/or poly(Q) proteins disrupted the proteasomal activity. Rescue of poly(Q) toxicity by hsromega-RNAi required normal proteasomal function. We suggest that hsromega-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 hsromega 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 hsromega RNA functions as a "hub" in cellular networks to maintain homeostasis by coordinating the functional availability of crucial cellular regulatory proteins.
Mallik
Moushami
M
Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, India.
Lakhotia
Subhash C
SC
D000818:Animals; D050882:CREB-Binding Protein / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005128:Eye Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D022661:RNA, Untranslated / Q000235:genetics; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism
D029721:Drosophila Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C402657:Hrb87F protein, Drosophila; D009687:Nuclear Proteins; D010455:Peptides; D022661:RNA, Untranslated; D025801:Ubiquitin; C097188:polyglutamine; D050882:CREB-Binding Protein; D046988:Proteasome Endopeptidase Complex