Unfolded protein response in Drosophila melanogaster: Role of IRE1/XBP1 pathway of UPR during differentiation and ER stress
Abstract
Unfolded protein response (UPR) is a group of adaptive signal transduction pathways elicited in response to ER stress caused by accumulation of misfolded proteins. UPR, specifically Ire1/Xbp1 pathway is highly conserved and plays an important role during normal development and ER stress. UPR upregulates and maintains the secretory pathway components during development and differentiation of professional secretory cells like plasma cells and pancreatic beta cells. Also, UPR components are important for proper regulation of ER stress in secretory cells. Mutations or loss of these components leads to unresolved ER stress and cell death, causing diseases like inflammatory bowel disease, juvenile diabetes. Recent studies indicated that UPR pathways are crucial for cell fate decision during development of many protein misfolding diseases and any compromise in ER stress response would tilt the balance towards apoptosis from adaptive response. Thus efficiency of UPR determines time of manifestation for diseases like diabetes and neurodegenerative diseases. It is thus important to understand the mechanism and regulation of UPR pathways. Since our current understanding of UPR is largely derived from cell culture experiments, there is a need for a good genetic model system like Drosophila to understand how a cell responds to ER stress in vivo. We designed a UPR reporter based on ER-stress specific endonuclease activity of Ire1 on Xbp1 mRNA. Our UPR reporter studies indicated that photoreceptors activate UPR during specific development stages, but not in adults. UPR activation is correlated with morphological and cellular changes that occur during photoreceptor development. With the same reporter we found that vitamin A deficiency, which leads to retention of rhodopsin 1 (Rh1) in photoreceptor ER, induces UPR. Similar studies showed that loss of Rh1-specific chaperone NinaA, which likewise leads to ER retention of Rh1, also activates UPR. Rhodopsin accumulates in the ER and fails to transport to the rhabdomeres in ninaA mutants lacking this essential Rh1-specific ER chaperone. Overexpression of spliced form of Xbp1 (Xbp1s) rescues rhodopsin maturation and transport to the rhabdomere. Xbp1s overexpression increases BiP levels and expression of dominant negative BiP compromised this rescue. As in other systems, Xbp1s expression causes extended ER cisternae in Drosophila photoreceptors. Thus, we propose that Xbp1s overexpression increases secretory pathway components including ER, and rescues rhodopsin transport in a BiP-dependent manner.
Degree
Ph.D.
Advisors
Ready, Purdue University.
Subject Area
Molecular biology|Genetics|Cellular biology
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