Seminar Abstract: The unfolded protein response (UPR) is a signaling network that adjusts the protein folding capacity of the endoplasmic reticulum (ER) according to need. The most conserved UPR sensor, IRE1α, spans the ER membrane and activates by oligomerization. IRE1α oligomers accumulate in dynamic foci. The structure of IRE1α foci in intact cells has been determined by cryogenic correlated light and electron microscopy combined with electron cryo-tomography. IRE1α oligomers localize to a network of narrow anastomosing ER tubes (diameter 28 nm) with complex branching topology. The lumen of the tubes contains protein filaments, likely composed of linear arrays of IRE1α lumenal domain dimers that resolved to 15 Å and are arranged in two intertwined, left-handed helices. There findings define a previously unrecognized ER subdomain and suggest positive feedback regulation in IRE1 signalling.