Activation of the endoplasmic reticulum stress sensor IRE1 by lipid perturbations during flavivirus infections. (360G-Wellcome-093764_Z_10_Z)

£606,020

IRE1 is an endoplasmic reticulum (ER) localized enzyme promoting lipid synthesis and ER membrane expansion. Flaviviruses have been shown to activate IRE1. This project aims to test the contribution of IRE1 activation to flavivirus-induced membrane remodelling and to study the mechanisms of flavivirus-induced IRE1 activation. IRE1 is activated by unfolded proteins accumulating in the ER lumen. However, the recently identified cytoplasmic Q-site of IRE1 which binds to hydrophobic molecules could a lso contribute to flavivirus-induced IRE1 activation. More precisely, virally-induced lipid perturbations could activate IRE1 by a direct stimulation of the cytoplasmic Q-site. To test this hypothesis, we will generate IRE1 mutants that are unable to respond to unfolded proteins or to stimulation through the Q-site. Using IRE1 knock-out cells rescued with the different IRE1 mutants, we will determine to which extent IRE1 activation by unfolded proteins or by stimulation through the Q-site contri bute to flavivirus-induced ER membrane remodelling. Finally, a small compound screen performed in the host laboratory has identified potential IRE1 Q-site ligands. We will test the ability of these molecules to modulate IRE1 activity. Given the heavy reliance of flavivirus replication on lipid metabolism and ER membrane modifications, we will evaluate the antiviral properties of these molecules.

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Grant Details

Amount Awarded 606020
Applicant Surname Volmer
Approval Committee Clinical Interview Committee
Award Date 2010-11-25T00:00:00+00:00
Financial Year 2010/11
Grant Programme: Title Intermediate Clinical Fellowship
Internal ID 093764/Z/10/Z
Lead Applicant Dr Romain Volmer
Partnership Value 606020
Planned Dates: End Date 2015-02-28T00:00:00+00:00
Planned Dates: Start Date 2011-03-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England
Sponsor(s) Prof David Ron