Fortilin binds IRE1α and prevents ER stress from signaling apoptotic cell death

Pinkaew, Decha; Chattopadhyay, Abhijnan; King, Matthew D.; Chunhacha, Preedakorn; Liu, Zhihe; Stevenson, Heather L.; Chen, Yanjie; Sinthujaroen, Patuma; McDougal, Owen M.; Fujise, Ken

doi:10.1038/s41467-017-00029-1

Cited by 66 publications

(66 citation statements)

References 82 publications

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“…However, so far, an involvement of TCTP in modulating ER-stress and the unfolded protein response (UPR) was not yet described. A recent paper by Pinkaew et al fills this gap (Pinkaew et al 2017), by reporting that TCTP (fortilin) binds to the cytoplasmic domain of the ER-stress sensor IRE1α, inhibiting its endonuclease (RNase) and protein kinase activities, and in this way protecting cells against apoptotic cell death. 2.…”

Section: Note Added In Proofmentioning

confidence: 99%

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

Bommer

2017

Results and Problems in Cell Differentiation

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The Translational Controlled Tumour Protein TCTP (gene symbol TPT1, also called P21, P23, Q23, fortilin or histamine-releasing factor, HRF) is a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes. It was first discovered about 35 years ago, and it took an extended period of time for its multiple functions to be revealed, and even today we do not yet fully understand all the details. Having witnessed most of this history, in this chapter, I give a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of this protein. TCTP is able to interact with a large number of other proteins and is therefore involved in many core cell biological processes, predominantly in the response to cellular stresses, such as oxidative stress, heat shock, genotoxic stress, imbalance of ion metabolism as well as other conditions. Mechanistically, TCTP acts as an anti-apoptotic protein, and it is involved in DNA-damage repair and in cellular autophagy. Thus, broadly speaking, TCTP can be considered a cytoprotective protein. In addition, TCTP facilitates cell division through stabilising the mitotic spindle and cell growth through modulating growth signalling pathways and through its interaction with the proteosynthetic machinery of the cell. Due to its activities, both as an anti-apoptotic protein and in promoting cell growth and division, TCTP is also essential in the early development of both animals and plants. Apart from its involvement in various biological processes at the cellular level, TCTP can also act as an extracellular protein and as such has been involved in modulating whole-body defence processes, namely in the mammalian immune system. Extracellular TCTP, typically in its dimerised form, is able to induce the release of cytokines and other signalling molecules from various types of immune cells. There are also several examples, where TCTP was shown to be involved in antiviral/antibacterial defence in lower animals. In plants, the protein appears to have a protective effect against phytotoxic stresses, such as flooding, draught, too high or low temperature, salt stress or exposure to heavy metals. The finding for the latter stress condition is corroborated by earlier reports that TCTP levels are considerably up-regulated upon exposure of earthworms to high levels of heavy metals. Given the involvement of TCTP in many biological processes aimed at maintaining cellular or whole-body homeostasis, it is not surprising that dysregulation of TCTP levels may promote a range of disease processes, foremost cancer. Indeed a large body of evidence now supports a role of TCTP in at least the most predominant types of human cancers. Typically, this can be ascribed to both the anti-apoptotic activity of the protein and to its function in promoting cell growth and division. However, TCTP also appears to be involved in the later stages of cancer progression, such ...

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Section: Note Added In Proofmentioning

confidence: 99%

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

Bommer

2017

Results and Problems in Cell Differentiation

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“…It is highly desirable to gain both pharmacological and genetic evidence before the field moves to clinical trials of candidate HRF inhibitors. However, genetic studies without affecting the function of intracellular TCTP are difficult if an experiment is conducted with TCTP conditional knockout (CKO) mice, including inducible CKO mice [40,66]. It is likely that the targeted cells may die because of their dependence of survival on TCTP.…”

Section: Discussionmentioning

confidence: 99%

“…It is likely that the targeted cells may die because of their dependence of survival on TCTP. With such limitations, RNA interference (siRNA or shRNA) may be better suited to in vitro and in vivo experiments [66]. An alternative approach is to use heterozygous TCTP KO mice.…”

Section: Discussionmentioning

confidence: 99%

Histamine-Releasing Factor, a New Therapeutic Target in Allergic Diseases

Kawakami

Kasakura

Kawakami

2019

Cells

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Histamine-releasing activities on human basophils have been studied as potential allergy-causing agents for four decades. An IgE-dependent histamine-releasing factor (HRF) was recently shown to interact with a subset of immunoglobulins. Peptides or recombinant proteins that block the interactions between HRF and IgE have emerged as promising anti-allergic therapeutics, as administration of them prevented or ameliorated type 2 inflammation in animal models of allergic diseases such as asthma and food allergy. Basic and clinical studies support the notion that HRF amplifies IgE-mediated activation of mast cells and basophils. We discuss how secreted HRF promotes allergic inflammation in vitro and in vivo complex disease settings.

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“…RNase activity of IRE1 in the presence of RNH1 or 4µ8C was assayed in vitro using a fluorescence method as described previously [22,58]. Briefly, 40 µL of recombinant human IRE1 (20 µg, OriGene) was pre-incubated for 30 min with 40 µL of various concentrations of recombinant human RNH1 (20 µg, OriGene) or 4µ8C (0,1 nM-1 µM) in RNase Assay Buffer (50 mM HEPES, 100 mM KOAc, 5 mM DTT, 5% glycerol, 0,005% Triton X-100, pH 7,2).…”

Section: In Vitro Ire1 Rnase Activity Assaymentioning

confidence: 99%

“…The control of IRE1 expression levels is also involved in IRE1 signaling either through the RIDD of its own mRNA [19], or its degradation mediated by Protein Disulfide Isomerase (PDI) A6 [20]. The formation of stable interaction with Bax inhibitor 1 (BI-1) or Fortilin with IRE1 inhibits its activity upon sustained ER stress [21,22]. However, all these mechanisms do not provide a clear mechanism for tight and direct regulation of the activity of IRE1 RNase.…”

Section: Introductionmentioning

confidence: 99%

Regulation of IRE1 RNase activity by the Ribonuclease inhibitor 1 (RNH1)

et al. 2018

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Adaptation to endoplasmic reticulum (ER) stress depends on the activation of the sensor inositolrequiring enzyme 1α (IRE1), an endoribonuclease that splices the mRNA of the transcription factor XBP1 (X-box-binding protein 1). To better understand the protein network that regulates the activity of the IRE1 pathway, we systematically screened the proteins that interact with IRE1 and identified a ribonuclease inhibitor called ribonuclease/angiogenin inhibitor 1 (RNH1). RNH1 is a leucine-rich repeat domains-containing protein that binds to and inhibits ribonucleases. Immunoprecipitation experiments confirmed this interaction. Docking experiments indicated that RNH1 physically interacts with IRE1 through its cytosolic RNase domain. Upon ER stress, the interaction of RNH1 with IRE1 in the ER increased at the expense of the nuclear pool of RNH1. Inhibition of RNH1 expression using siRNA mediated RNA interference upon ER stress led to an increased splicing activity of XBP1. Modulation of IRE1 RNase activity by RNH1 was recapitulated in a cell-free system, suggesting direct regulation of IRE1 by RNH. We conclude that RNH1 attenuates the activity of IRE1 by interacting with its ribonuclease domain. These findings have implications for understanding the molecular mechanism by which IRE1 signaling is attenuated upon ER stress.

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Fortilin binds IRE1α and prevents ER stress from signaling apoptotic cell death

Cited by 66 publications

References 82 publications

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

Histamine-Releasing Factor, a New Therapeutic Target in Allergic Diseases

Regulation of IRE1 RNase activity by the Ribonuclease inhibitor 1 (RNH1)

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