Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering.

Autor:	Kettel P; Max Perutz Laboratories Vienna, Vienna BioCenter, Vienna, Austria.; Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria., Marosits L; Max Perutz Laboratories Vienna, Vienna BioCenter, Vienna, Austria.; Medical University of Vienna, Vienna, Austria., Spinetti E; Frankfurt Institute for Advanced Studies, Frankfurt, Germany.; Institute of Biophysics, Goethe University, Frankfurt, Germany., Rechberger M; Max Perutz Laboratories Vienna, Vienna BioCenter, Vienna, Austria., Giannini C; Institute of Science and Technology Austria, Klosterneuburg, Austria., Radler P; Institute of Science and Technology Austria, Klosterneuburg, Austria., Niedermoser I; Max Perutz Laboratories Vienna, Vienna BioCenter, Vienna, Austria.; Medical University of Vienna, Vienna, Austria., Fischer I; Max Perutz Laboratories Vienna, Vienna BioCenter, Vienna, Austria., Versteeg GA; Max Perutz Laboratories Vienna, Vienna BioCenter, Vienna, Austria.; Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria., Loose M; Institute of Science and Technology Austria, Klosterneuburg, Austria., Covino R; Frankfurt Institute for Advanced Studies, Frankfurt, Germany.; IMPRS on Cellular Biophysics, Frankfurt, Germany., Karagöz GE; Max Perutz Laboratories Vienna, Vienna BioCenter, Vienna, Austria. guelsuen.karagoez@meduniwien.ac.at.; Medical University of Vienna, Vienna, Austria. guelsuen.karagoez@meduniwien.ac.at.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Oct; Vol. 43 (20), pp. 4668-4698. Date of Electronic Publication: 2024 Sep 04.
DOI:	10.1038/s44318-024-00207-0
Abstrakt:	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 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 role as a common strategy in regulating protein assembly on membranes. (© 2024. The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu