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

J 2024

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

KETTEL, Paulina; Laura MAROSITS; Elena SPINETTI; Michael RECHBERGER; Caterina GIANNINI et. al.

Základní údaje

Originální název

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

Autoři

Vydání

EMBO Journal, Hoboken (USA), WILEY-BLACKWELL, 2024, 0261-4189

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 8.300

Kód RIV

RIV/00216224:90242/24:00139153

Organizační jednotka

CIISB III

DOI

https://doi.org/10.1038/s44318-024-00207-0

UT WoS

001306286100002

EID Scopus

2-s2.0-85203078172

Klíčová slova anglicky

Unfolded Protein Response; IRE1; Supported Lipid Bilayers; Biomolecular Condensates

Štítky

CF BIC, ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 24. 3. 2025 00:37, Mgr. Eva Dubská

Anotace

V originále

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 IRE1 alpha forms biomolecular condensates in vitro. IRE1 alpha LD condensates were stabilized both by binding to unfolded polypeptides as well as by tethering to model membranes, suggesting their role in assembling IRE1 alpha into signaling-competent stable clusters. Molecular dynamics simulations indicated that weak multivalent interactions drive IRE1 alpha LD clustering. Mutagenesis experiments identified disordered regions in IRE1 alpha LD to control its clustering in vitro and in cells. Importantly, dysregulated clustering of IRE1 alpha mutants led to defects in IRE1 alpha signaling. Our results revealed that disordered regions in IRE1 alpha LD control its clustering and suggest their role as a common strategy in regulating protein assembly on membranes.

Návaznosti

90242, velká výzkumná infrastruktura

Název: CIISB III

Citovat

KETTEL, Paulina; Laura MAROSITS; Elena SPINETTI; Michael RECHBERGER; Caterina GIANNINI; Philipp RADLER; Isabell NIEDERMOSER; Irmgard FISCHER; Gijs A VERSTEEG; Martin LOOSE; Roberto COVINO a G Elif KARAGOEZ. Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering. EMBO Journal. Hoboken (USA): WILEY-BLACKWELL, 2024, roč. 43, č. 20, s. 4668-4698. ISSN 0261-4189. Dostupné z: https://doi.org/10.1038/s44318-024-00207-0.

@article{2485957,
   author = {Kettel, Paulina and Marosits, Laura and Spinetti, Elena and Rechberger, Michael and Giannini, Caterina and Radler, Philipp and Niedermoser, Isabell and Fischer, Irmgard and Versteeg, Gijs A and Loose, Martin and Covino, Roberto and Karagoez, G Elif},
   article_location = {Hoboken (USA)},
   article_number = {20},
   doi = {https://doi.org/10.1038/s44318-024-00207-0},
   keywords = {Unfolded Protein Response; IRE1; Supported Lipid Bilayers; Biomolecular Condensates},
   language = {eng},
   issn = {0261-4189},
   journal = {EMBO Journal},
   title = {Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering},
   url = {https://www.embopress.org/doi/full/10.1038/s44318-024-00207-0},
   volume = {43},
   year = {2024}
}

TY  - JOUR
ID  - 2485957
AU  - Kettel, Paulina - Marosits, Laura - Spinetti, Elena - Rechberger, Michael - Giannini, Caterina - Radler, Philipp - Niedermoser, Isabell - Fischer, Irmgard - Versteeg, Gijs A - Loose, Martin - Covino, Roberto - Karagoez, G Elif
PY  - 2024
TI  - Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering
JF  - EMBO Journal
VL  - 43
IS  - 20
SP  - 4668-4698
EP  - 4668-4698
PB  - WILEY-BLACKWELL
SN  - 02614189
KW  - Unfolded Protein Response
KW  - IRE1
KW  - Supported Lipid Bilayers
KW  - Biomolecular Condensates
UR  - https://www.embopress.org/doi/full/10.1038/s44318-024-00207-0
N2  - 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 IRE1 alpha forms biomolecular condensates in vitro. IRE1 alpha LD condensates were stabilized both by binding to unfolded polypeptides as well as by tethering to model membranes, suggesting their role in assembling IRE1 alpha into signaling-competent stable clusters. Molecular dynamics simulations indicated that weak multivalent interactions drive IRE1 alpha LD clustering. Mutagenesis experiments identified disordered regions in IRE1 alpha LD to control its clustering in vitro and in cells. Importantly, dysregulated clustering of IRE1 alpha mutants led to defects in IRE1 alpha signaling. Our results revealed that disordered regions in IRE1 alpha LD control its clustering and suggest their role as a common strategy in regulating protein assembly on membranes.
ER  -

KETTEL, Paulina; Laura MAROSITS; Elena SPINETTI; Michael RECHBERGER; Caterina GIANNINI; Philipp RADLER; Isabell NIEDERMOSER; Irmgard FISCHER; Gijs A VERSTEEG; Martin LOOSE; Roberto COVINO a G Elif KARAGOEZ. Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering. \textit{EMBO Journal}. Hoboken (USA): WILEY-BLACKWELL, 2024, roč.~43, č.~20, s.~4668-4698. ISSN~0261-4189. Dostupné z: https://doi.org/10.1038/s44318-024-00207-0.

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