title: BiP-bound and nonclustered mode of Ire1 evokes a weak but sustained unfolded protein response.
abstract: 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.
authors: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors: Yuki
authors: Y
authors: Ishiwata-Kimata
authors: Thanyarat
authors: T
authors: Promlek
authors: Kenji
authors: K
authors: Kohno
authors: Yukio
authors: Y
authors: Kimata
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007294:Inositol / Q000172:deficiency; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D011485:Protein Binding; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058767:Protein Unfolding; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D005656:Fungal Proteins; D018840:HSP70 Heat-Shock Proteins; C060153:KAR2 protein, yeast; D008562:Membrane Glycoproteins; D029701:Saccharomyces cerevisiae Proteins; D007294:Inositol; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases