Journal
GENES TO CELLS
Volume 18, Issue 4, Pages 288-301Publisher
WILEY
DOI: 10.1111/gtc.12035
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Funding
- Ministry of Education, Culture, Sports, Science Technology [22657030, 21112516, 24370081, 19058010, 20380062]
- Japan Society for the Promotion of Science [22657030, 21112516, 24370081, 19058010, 20380062]
- Noda Institute for Scientific Research
- Grants-in-Aid for Scientific Research [20380062, 19058010, 25892018, 21112516, 22657030] Funding Source: KAKEN
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In eukaryotic cells under nonstressed conditions, the endoplasmic reticulum (ER)-located molecular chaperone BiP is associated with an ER-membrane protein Ire1 to inhibit its self-association. While ER stress leads Ire1 to form transiently BiP-unbound clusters, which strongly evoke the unfolded protein response (UPR), here we propose an alternative activation status of Ire1. When yeast cells are physiologically ER-stressed by inositol depletion for a prolonged time, the UPR is weakly activated in a sustained manner after a transient peak of activation. During persistent stress, Ire1 foci disappear, while Ire1 continues to be self-associated. Under these conditions, Ire1 may be activated as a homo-dimer, as it shows considerable activity even when carrying the W426A mutation, which allows Ire1 to form homo-dimers but not clusters. Unlike the Ire1 clusters, the nonclustered active form seems to be associated with BiP. An Ire1 mutant not carrying the BiP-association site continued to form clusters and to be activated strongly even after long-term stress. Similar observations were obtained when cells were ER-stressed by dithiothreitol. We thus propose that upon persistent ER stress, Ire1 is weakly and continuously activated in a nonclustered form through its (re)association with BiP, which disperses the Ire1 clusters.
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