The 99th Annual Meeting of the Japanese Pharmacological Society

Chair:Minoru Wakamori(Tohoku University Graduate School of Dentistry)

The endoplasmic reticulum (ER) unfolded protein response (UPR) is tuned by the balance between unfolded proteins and chaperones. An imbalance favouring unfolded proteins is referred to as ER stress and is a feature that contributes broadly to pathophysiology. Eukaryotes are endowed with signal transduction pathways that recognise ER stress and trigger downstream rectifying responses. Collectively these are referred to as the Unfolded Protein Response, which in animal cells is comprised of three strands mediated by different ER-localised stress transducers: IRE1, PERK and ATF6. Whilst the downstream effector mechanisms engaged by these three are well understood, the upstream-most event(s) that couples the activity of the transducers to the level of ER stress is less well understood. Here, I will review the prevailing ideas regarding this question and provide a perspective arising from recent structural and biochemical research on a mammalian isoform of IRE1.