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      An unfolded protein-induced conformational switch activates mammalian IRE1


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          The unfolded protein response (UPR) adjusts the cell’s protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α’s ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD’s MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1’s activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization.

          eLife digest

          Proteins are long string-like molecules that fold into specific three-dimensional shapes. Most proteins that a cell uses to communicate with its environment are folded within a part of the cell called the endoplasmic reticulum. Dedicated sensor proteins in this cellular compartment track this process to make sure that it continues to meet the cell’s demand for protein folding. If it cannot meet the demand, unfolded or poorly folded proteins build up, which stresses the cell.

          IRE1 is a sensor protein that detects stress in the endoplasmic reticulum. It is found in a range of organisms from yeast to humans, where it spans the membrane that encloses the endoplasmic reticulum. When unfolded proteins accumulate, IRE1 proteins come together and form so-called oligomers. The IRE1 oligomers then become active and send signals outside of the endoplasmic reticulum. These signals adjust the cell’s protein-folding capacity according to its needs at that time.

          The yeast version of IRE1 directly recognizes unfolded proteins in the endoplasmic reticulum. Yet, its human counterpart was found to have a different three-dimensional structure, which suggested that it might use a different mechanism to detect the stress.

          Now, Karagöz et al. show that, as in yeast, the sensor part of human IRE1 does indeed bind to unfolded proteins directly. This binding causes this part of the protein to engage other copies of IRE1 and form the oligomers. To understand this interaction in more detail, Karagöz et al. used a technique called nuclear magnetic resonance spectroscopy to monitor changes in the shape of proteins. These observations revealed that binding to an unfolded protein causes other parts of IRE1 protein to change shape. In turn, these shape changes act as a switch that causes the oligomers to form. Stopping the sensor domains from forming oligomers inactivated the IRE1 protein in mammalian cells; this rendered IRE1 unresponsive to stress within the endoplasmic reticulum.

          The regulation of IRE1 affects many health disorders, including diabetes, cancer and neurodegenerative diseases. By showing that unfolded proteins switch IRE1 into its active, oligomeric state, these findings might lead to new approaches to manipulate IRE1’s activity with small molecules to help to treat these diseases.

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          Most cited references46

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          Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase.

          The transcription of genes encoding soluble proteins that reside in the endoplasmic reticulum (ER) is induced when unfolded proteins accumulate in the ER. Thus, an intracellular signal transduction pathway must exist that mediates communication between the ER lumen and the nucleus. We have identified a gene in S. cerevisiae, IRE1, that is required for this pathway: ire1- mutants cannot activate transcription of KAR2 and PDI1, which encode the ER resident proteins BiP and protein disulfide isomerase. Moreover, IRE1 is essential for cell viability under stress conditions that cause unfolded proteins to accumulate in the ER. IRE1 encodes a transmembrane serine/threonine kinase that we propose transmits the unfolded protein signal across the ER or inner nuclear membrane. IRE1 is also required for inositol prototrophy, suggesting that the induction of ER resident proteins is coupled to the biogenesis of new ER membrane.
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            XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks.

            Using genome-wide approaches, we have elucidated the regulatory circuitry governed by the XBP1 transcription factor, a key effector of the mammalian unfolded protein response (UPR), in skeletal muscle and secretory cells. We identified a core group of genes involved in constitutive maintenance of ER function in all cell types and tissue- and condition-specific targets. In addition, we identified a cadre of unexpected targets that link XBP1 to neurodegenerative and myodegenerative diseases, as well as to DNA damage and repair pathways. Remarkably, we found that XBP1 regulates functionally distinct targets through different sequence motifs. Further, we identified Mist1, a critical regulator of differentiation, as an important target of XBP1, providing an explanation for developmental defects associated with XBP1 loss of function. Our results provide a detailed picture of the regulatory roadmap governed by XBP1 in distinct cell types as well as insight into unexplored functions of XBP1.
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              The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response.

              The endoplasmic reticulum (ER) communicates with the nucleus through the unfolded protein response (UPR), which senses accumulation of unfolded proteins in the ER lumen and leads to increased transcription of genes encoding ER-resident chaperones. As a key regulatory step in this signaling pathway, the mRNA encoding the UPR-specific transcription factor Hac1p becomes spliced by a unique mechanism that requires tRNA ligase but not the spliceosome. Splicing is initiated upon activation of Ire1p, a transmembrane kinase that lies in the ER and/or inner nuclear membrane. We show that Ire1p is a bifunctional enzyme: in addition to being a kinase, it is a site-specific endoribonuclease that cleaves HAC1 mRNA specifically at both splice junctions. The addition of purified tRNA ligase completes splicing; we therefore have reconstituted HAC1 mRNA splicing in vitro from purified components.

                Author and article information

                Role: Reviewing Editor
                eLife Sciences Publications, Ltd
                03 October 2017
                : 6
                : e30700
                [1 ]deptDepartment of Biochemistry and Biophysics Howard Hughes Medical Institute, University of California, San Francisco San FranciscoUnited States
                [2 ]deptDepartment of Molecular, Cellular, and Biomedical Sciences University of New Hampshire DurhamUnited States
                University of Toronto Canada
                University of Toronto Canada
                Author notes

                Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, United States.


                BioMarin Pharmaceutical Inc., San Rafael, United States.

                © 2017, Karagöz et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                : 27 July 2017
                : 02 October 2017
                Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;
                Award ID: CLF #1307367
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Research Article
                Biophysics and Structural Biology
                Custom metadata
                ER-stress sensing mechanism of the unfolded protein response sensor/transducer IRE1 is conserved from yeast to mammals, where in mammals, unfolded protein binding to IRE1's ER lumenal domain is coupled to its oligomerization and activation through an allosteric conformational change.

                Life sciences
                ire1,unfolded protein response,er-stress,nuclear magnetic resonance spectroscopy,mouse


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