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Vortrag von Elif Karagöz

Vortragstitel: "Unique mechanisms for sensing the proteotoxic stress in the endoplasmic reticulum"
Anlass: SFB - Seminar
Beginn: 23.01.2025 - 16:15 Uhr
Ort: CellNanOs, 38/201

Über die Vortragende: Dr. Elif Karagöz forscht im Department für Biochemie und Zellbiologie der Universität Wien.

Conserved signaling cascades monitor protein-folding homeostasis to ensure proper cellular function. One of the evolutionary conserved key players is IRE1, which maintains endoplasmic reticulum (ER) homeostasis through the unfolded protein response (UPR). Upon accumulation of misfolded proteins in the ER, IRE1 forms clusters on the ER membrane to initiate UPR signaling. What regulates IRE1 cluster formation is not fully understood. Here, we show that the ER lumenal domain (LD) of human IRE1α forms biomolecular condensates in vitro. IRE1α LD condensates were stabilized both by binding to unfolded polypeptides as well as by tethering IRE1 αLD to model membranes, suggesting their role in assembling IRE1α into signaling-competent stable clusters. Molecular dynamics simulations indicated that weak multivalent interactions drive IRE1α LD clustering. Mutagenesis experiments identified disordered regions in IRE1α LD to control its clustering in vitro and in cells. Importantly, dysregulated clustering of IRE1α mutants led to defects in IRE1α signaling. Our results revealed that disordered regions in IRE1α LD control its clustering and suggest their regulatory role to tune IRE1 activation on membranes.