[Frontier Leaders] Mechanisms that maintain protein folding homeostasis in the endoplasmic reticulum | David Ron

Frontier Leaders Seminar

Title: Mechanisms that maintain protein folding homeostasis in the endoplasmic reticulum

Speaker: David Ron

Affiliation: University of Cambridge

Abstract:

A transcriptional and translational program that strives to match the complement of chaperones in the endoplasmic reticulum (ER) to the burden of unfolded proteins in the early secretory pathway (the Unfolded Protein Response, UPR) has long been known to exist and its functional importance has been showcased by genetic and pharmacological manipulations. Here, I shall discuss some recently-gained insights into the mechanisms by which one mammalian UPR transducer, the ER-localized kinase endonuclease IRE1α, is activated by an imbalance between ER chaperones and unfolded proteins. Time permitting I shall also address the limitations imposed by the latency inherent in the UPR as a gene expression program and how it might be resolved by post-translational adaptations that operate on a shorter time scale. This will be exemplified by observations on an ER-localized post-translational circuitry that tunes the activity of the ER’s resident Hsp70 protein, BiP, to rapid fluctuations in unfolded protein load.