The activated endoplasmic reticulum stress sensor IRE1 oligomerizes into filaments contained in 30 nm membrane tubes of complex topology

Abstract

The unfolded protein response (UPR) is an intracellular signaling network that adjusts the abundance and protein folding capacity of the endoplasmic reticulum (ER) according to need. The most conversed branch of the UPR is mediated by the ER‐resident transmembrane kinase/endoribonuclease IRE1. It senses unfolded protein accumulation within the ER and transduces the signal via a non‐conventional mRNA splicing mechanism. In response to direct binding of unfolded proteins in the ER lumen, IRE1 activates by oligomerization and accumulates in dynamic foci. IRE1 foci are not autophagosomes as they did not colocalize with the autophagosomal marker LC3. Fluorescence recovery after photobleaching (FRAP) experiments indicate that IRE1 molecules in the foci remain in equilibrium with IRE1 molecules in the surrounding ER network. We determined the structure of IRE1 foci in cells by whole cell correlative light – electron tomography. Our results show that IRE1 oligomers induce membrane deformations, leading to the protrusion of narrow 30 nm ribosome‐free tubes that remain connected to the ER and are twisted into glomeruli of complex topology. The tubes contain two parallel filaments in their lumen, likely representing oligomerized IRE1 ER‐lumenal domains. Taken together, our findings define a previously unrecognized subdomain of the ER membrane and shed new light on the structure and organization of active mammalian IRE1 inside the cell.

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