Activation of mammalian IRE1α upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins

Oikawa, Daisuke; Kimata, Yukio; Kohno, Kenji; Iwawaki, Takao

doi:10.1016/j.yexcr.2009.06.009

Cited by 154 publications

(145 citation statements)

References 28 publications

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“…Like mammalian IRE1, the luminal domain of yeast IRE1 also binds to BiP, which dissociates upon stress (Okamura et al, 2000), but the importance of BiP dissociation in activating the yeast UPR has been debated (Kimata et al, 2004(Kimata et al, , 2007Pincus et al, 2010). In addition, the luminal domain of yeast IRE1, unlike that of mammalian IRE1 (Oikawa et al, 2009), directly binds to unfolded proteins (Kimata et al, 2007;Gardner and Walter, 2011). Once activated, the three mammalian ER-stress transducers act in a coordinated manner to restore ER homeostasis, not only by increasing the expression of genes encoding chaperones -i.e.…”

Section: The Unfolded Protein Responsementioning

confidence: 99%

Surviving protein quality control catastrophes – from cells to organisms

Schneider

Bertolotti

2015

Journal of Cell Science

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Organisms have evolved mechanisms to cope with and adapt to unexpected challenges and harsh conditions. Unfolded or misfolded proteins represent a threat for cells and organisms, and the deposition of misfolded proteins is a defining feature of many age-related human diseases, including the increasingly prevalent neurodegenerative diseases. These protein misfolding diseases are devastating and currently cannot be cured, but are hopefully not incurable. In fact, the aggregation-prone and potentially harmful proteins at the origins of protein misfolding diseases are expressed throughout life, whereas the diseases are late onset. This reveals that cells and organisms are normally resilient to disease-causing proteins and survive the threat of misfolded proteins up to a point. This Commentary will outline the limits of the cellular resilience to protein misfolding, and discuss the possibility of pushing these limits to help cells and organisms to survive the threat of misfolding proteins and to avoid protein quality control catastrophes.

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Section: The Unfolded Protein Responsementioning

confidence: 99%

Surviving protein quality control catastrophes – from cells to organisms

Schneider

Bertolotti

2015

Journal of Cell Science

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“…Several ER transmembrane proteins act as ER stress sensors. The oldest among these, inositol-requiring enzyme 1 (IRE1), is conserved from yeast to mammals and possesses a luminal sensor domain (10)(11)(12)(13)(14) and a cytosolic effector domain (15,16). In yeast Ire1p's effector is a highly sequence-specific RNase that participates in the regulated first step of an unconventional splicing event that activates the Homologous to Atf/Creb 1 (HAC1) mRNA to encode a potent transactivator of UPR target genes (8,(17)(18)(19).…”

mentioning

confidence: 99%

Negative feedback by IRE1β optimizes mucin production in goblet cells

Tsuru

Fujimoto

Takahashi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In mammals, the prototypical endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) has diverged into two paralogs. IRE1α is broadly expressed and mediates the unconventional splicing of X-box binding protein 1 (XBP1) mRNA during ER stress. By contrast, IRE1β is expressed selectively in the digestive tract, and its function remains unclear. Here, we report that IRE1β plays a distinctive role in mucin-secreting goblet cells. In IRE1β −/− mice, aberrant mucin 2 (MUC2) accumulated in the ER of goblet cells, accompanied by ER distension and elevated ER stress signaling such as increased XBP1 mRNA splicing. In contrast, conditional IRE1α −/− mice showed no such ER distension but a marked decrease in spliced XBP1 mRNA. mRNA stability assay revealed that MUC2 mRNA was greatly stabilized in IRE1β −/− mice. These findings suggest that in goblet cells, IRE1β, but not IRE1α, promotes efficient protein folding and secretion in the ER by optimizing the level of mRNA encoding their major secretory product, MUC2.inflammatory bowel disease | unfolded protein response

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“…The IRE1α-null MEFs were transfected with vectors encoding wild-type hemagglutinin (HA)-tagged IRE1α or cysteine mutants. 17) MeHg-induced inhibition of IRE1α en- donuclease activity was significantly ameliorated in the MEFs that expressed IRE1α (C931S), but not the IRE1α (C951S) mutants, thereby suggesting that C931 in IRE1α could be a predominant target of MeHg (Figs. 1B, C).…”

Section: Resultsmentioning

confidence: 98%

Modulation of Unfolded Protein Response by Methylmercury

Hiraoka

Nakahara

Kaneko

et al. 2017

Biological & Pharmaceutical Bulletin

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Methylmercury (MeHg) results in cell death through endoplasmic reticulum (ER) stress. Previously, we reported that MeHg induces S-mercuration at cysteine 383 or 386 in protein disulfide isomerase (PDI), and this modification induces the loss of enzymatic activity. Because PDI is a key enzyme for the maturation of nascent protein harboring a disulfide bond, the disruption in PDI function by MeHg results in ER stress via the accumulation of misfolded proteins. However, the effects of MeHg on unfolded protein response (UPR) sensors and their signaling remain unclear. In the present study, we show that UPR is regulated by MeHg. We found that MeHg specifically attenuated inositol-requiring enzyme 1α (IRE1α)-x-box binding protein 1 (XBP1) branch, but not the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcriptional factor 6 (ATF6) branches. Treatment with GSK2606414, a specific PERK inhibitor, significantly inhibited MeHg-induced cell death. These findings suggest that MeHg exquisitely regulates UPR signaling involved in cell death.

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Activation of mammalian IRE1α upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins

Cited by 154 publications

References 28 publications

Surviving protein quality control catastrophes – from cells to organisms

Surviving protein quality control catastrophes – from cells to organisms

Negative feedback by IRE1β optimizes mucin production in goblet cells

Modulation of Unfolded Protein Response by Methylmercury

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