[SCAN] Post-transcriptional regulation of Drosophila Xbp1 a mediator of the ER stress response

SCAN

Title: Post-transcriptional regulation of Drosophila Xbp1 a mediator of the ER stress response

Speaker: Fátima Cairrão

Affiliation: Pedro Domingos Lab

Abstract:

Various environmental stresses and changes in physiological conditions can result in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) lumen, a cellular condition named ER stress.  To counteract ER stress and restore normal protein folding capacity cells activate an unfolding protein response (UPR). Three signaling pathways are involved in the UPR that are activated by different ER transmembrane protein sensors: the inositol requiring enzyme 1 (IRE1α), the PKR-like ER kinase (PERK) and the activating transcription factor 6 (ATF6).

 IRE1α plays a major role in the initiation of UPR through the activation of the downstream transcriptional factor XBP1. The IRE1 signaling may be particularly helpful in preventing chronic ER stress, a situation that can cause cell death and is proposed to trigger the pathogenesis of many human diseases. Homeostasis of the cells during the UPR requires that the levels of the Xbp1 transcription factor must be properly localized to the ER and modulated to respond adequately to sudden stress conditions or developmental clues. Analysis of the Drosophila Xbp1 3’UTR region sequence shows that it contains several regulatory sequences, namelly 2 putative binding sequences for the RNA binding protein Pumilio, suggesting that Xbp1 mRNA could be a target for Pumilio posttranscriptional regulation. Also several studies report interplay between Pumilio and microRNAS. Similarly we have found in the 3’UTR of Xbp1 mRNA predicted sites for dmir-87 (evolutionary conserved) in the vicinity of Pumilio binding sites that suggest an interaction between both elements. Our data shows that Pumilio can modulate the stability of Drosophila Xbp1s mRNA and its expression during pupal stages. Also previous studies by TAP affinity pulldown and our recent results revealed that xbp1 mRNA is enriched in transgenic flies expressing a TAP tagged Pumilio RNA binding domain.

These results suggest that control of Xbp1spliced during the UPR response is mediated by an interplay of the Xbp1 3’UTR with Pumilio. Our ongoing projects include analysing the effects of Pumilio phosphorylation state during the UPR on the regulation of Xbp1 and its localization to the vicinity of the ER membrane.