Mammalian ER stress sensor IRE1β specifically down-regulates the synthesis of secretory pathway proteins

Nakamura, Daisuke; Tsuru, Akio; Ikegami, Kentaro; Imagawa, Yusuke; Fujimoto, Naoko; Kohno, Kenji

doi:10.1016/j.febslet.2010.12.002

Cited by 42 publications

(47 citation statements)

References 19 publications

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“…The latter findings do not support the hypothesis that IRE1β’s role is limited to the destruction of mRNAs encoding secreted proteins, as previously described. 45 Although the present study has not directly addressed protein translation, our data suggest that IRE1β expression is necessary to maintain the secretory capacity of mucin-producing cells, under both basal and stimulated conditions (Figures 3, 5–8). …”

Section: Discussionmentioning

confidence: 64%

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The ER stress transducer IRE1β is required for airway epithelial mucin production

et al. 2013

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Inflammation of human bronchial epithelia (HBE) activates the endoplasmic reticulum (ER) stress transducer inositolrequiring enzyme 1 (IRE1)α, resulting in IRE1α-mediated cytokine production. Previous studies demonstrated ubiquitous expression of IRE1α and gut-restricted expression of IRE1β.We found that IRE1β is also expressed in HBE, is absent in human alveolar cells, and is upregulated in cystic fibrosis and asthmatic HBE. Studies with Ire1β−/− mice and Calu-3 airway epithelia exhibiting IRE1β knockdown or overexpression revealed that IRE1β is expressed in airway mucous cells, is functionally required for airway mucin production, and this function is specific for IRE1β vs. IRE1α. IRE1β-dependent mucin production is mediated, at least in part, by activation of the transcription factor X-box binding protein-1 (XBP-1) and the resulting XBP-1-dependent transcription of anterior gradient homolog 2, a gene implicated in airway and intestinal epithelial mucin production. These novel findings suggest that IRE1β is a potential mucous cell-specific therapeutic target for airway diseases characterized by mucin overproduction.

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Section: Discussionmentioning

confidence: 64%

“…This translational repression was later shown to be specific to ER-associated (as opposed to cytoplasmic) translation. 45 These studies were conducted in non-mucous-producing cells, and they may not reflect a completely accurate picture of IRE1β function.…”

Section: Discussionmentioning

confidence: 99%

The ER stress transducer IRE1β is required for airway epithelial mucin production

et al. 2013

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“…Analysis of our previous microarray data and subsequent qPCR analysis comparing transcripts levels between WT and ire1a/b clearly demonstrated the occurrence of RIDD in Arabidopsis in addition to Drosophila (5) and mammalian cells (6,7,25); that is, most genes (94.4%) down-regulated by Tm in WT, but not in ire1a/b, encoded the secretory pathway proteins, namely proteins with predicted SS/TM. Consistent with our previous study indicating the functional redundancy of IRE1A and IRE1B for the cytoplasmic splicing of bZIP60 (10), both IRE1A and IRE1B were revealed to contribute to the degradation of PR-4, PRX34, and AT1G78850 mRNAs.…”

Section: Discussionmentioning

confidence: 99%

Defects in IRE1 enhance cell death and fail to degrade mRNAs encoding secretory pathway proteins in the Arabidopsis unfolded protein response

Mishiba

Nagashima

Suzuki

et al. 2013

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

167

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The unfolded protein response (UPR) is a cellular response highly conserved in eukaryotes to obviate accumulation of misfolded proteins in the endoplasmic reticulum (ER). Inositol-requiring enzyme 1 (IRE1) catalyzes the cytoplasmic splicing of mRNA encoding bZIP transcription factors to activate the UPR signaling pathway. Arabidopsis IRE1 was recently shown to be involved in the cytoplasmic splicing of bZIP60 mRNA. In the present study, we demonstrated that an Arabidopsis mutant with defects in two IRE1 paralogs showed enhanced cell death upon ER stress compared with a mutant with defects in bZIP60 and wild type, suggesting an alternative function of IRE1 in the UPR. Analysis of our previous microarray data and subsequent quantitative PCR indicated degradation of mRNAs encoding secretory pathway proteins by tunicamycin, DTT, and heat in an IRE1-dependent manner. The degradation of mRNAs localized to the ER during the UPR was considered analogous to a molecular mechanism referred to as the regulated IRE1-dependent decay of mRNAs reported in metazoans. Another microarray analysis conducted in the condition repressing transcription with actinomycin D and a subsequent Gene Set Enrichment Analysis revealed the regulated IRE1-dependent decay of mRNAs-mediated degradation of a significant portion of mRNAs encoding the secretory pathway proteins. In the mutant with defects in IRE1, genes involved in the cytosolic protein response such as heat shock factor A2 were upregulated by tunicamycin, indicating the connection between the UPR and the cytosolic protein response.heat stress | protein folding | bioinformatics T he unfolded protein response (UPR) or the endoplasmic reticulum (ER) stress response is a cellular response that is highly conserved in eukaryotes to obviate accumulation of misfolded proteins and to alleviate protein overload in the ER (1-3). Inositol-requiring enzyme 1 (IRE1), which is the primary transducer of the UPR in various organisms, catalyzes the unconventional or cytoplasmic splicing of mRNAs encoding bZIP transcription factors to up-regulate the UPR-related genes, such as genes for the ER-resident molecular chaperones, through its ribonuclease domain. The cytoplasmic splicing by IRE1 activates the bZIP transcription factors HAC1, XBP1, and bZIP60 in yeast, animals, and plants, respectively, by producing active proteins. Although the fundamental mechanism of the cytoplasmic splicing by IRE1 appears to be highly conserved, the mechanism of transcription factor activation is diverse among organisms (4).In addition to the cytoplasmic splicing of mRNAs for transcription factors, other functions of metazoan IRE1 have been reported. One such function is the degradation of mRNAencoding proteins in the secretory pathway referred to as regulated IRE1-dependent decay (RIDD) (5-7). RIDD is considered to contribute to reducing the amount of proteins entering the ER in the UPR. The metazoan UPR has an alternative mechanism to reduce the amount of protein entering the ER, and this mechanism is regulated by PKR-li...

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“…It is known that IRE1␤ contributes to regulation of lipoprotein assembly in intestinal CaCo-2 epithelial cells by suppressing mRNA of an ER chaperon (73). IRE1␤ also selectively degrades the mRNA of secretory pathway proteins in intestinal epithelial cells and has slightly different substrate specificity from IRE␣ (261). The intestines and lungs have evolved sophisticated defensive immune mechanisms to deal with repeated exposure to pathogens, environmental insults, and toxins, and the restricted tissue expression of IRE1␤ to intestinal and respiratory tracts may contribute to ER stress adaptations in these microenvironments.…”

Section: A Chop Activities: Friend or Foe?mentioning

confidence: 99%

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

Iskander

Osuchowski

Stearns-Kurosawa

et al. 2013

Physiological Reviews

357

335

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Sepsis represents the host's systemic inflammatory response to a severe infection. It causes substantial human morbidity resulting in hundreds of thousands of deaths each year. Despite decades of intense research, the basic mechanisms still remain elusive. In either experimental animal models of sepsis or human patients, there are substantial physiological changes, many of which may result in subsequent organ injury. Variations in age, gender, and medical comorbidities including diabetes and renal failure create additional complexity that influence the outcomes in septic patients. Specific system-based alterations, such as the coagulopathy observed in sepsis, offer both potential insight and possible therapeutic targets. Intracellular stress induces changes in the endoplasmic reticulum yielding misfolded proteins that contribute to the underlying pathophysiological changes. With these multiple changes it is difficult to precisely classify an individual's response in sepsis as proinflammatory or immunosuppressed. This heterogeneity also may explain why most therapeutic interventions have not improved survival. Given the complexity of sepsis, biomarkers and mathematical models offer potential guidance once they have been carefully validated. This review discusses each of these important factors to provide a framework for understanding the complex and current challenges of managing the septic patient. Clinical trial failures and the therapeutic interventions that have proven successful are also discussed.

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Mammalian ER stress sensor IRE1β specifically down-regulates the synthesis of secretory pathway proteins

Cited by 42 publications

References 19 publications

The ER stress transducer IRE1β is required for airway epithelial mucin production

The ER stress transducer IRE1β is required for airway epithelial mucin production

Defects in IRE1 enhance cell death and fail to degrade mRNAs encoding secretory pathway proteins in the Arabidopsis unfolded protein response

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

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