Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α

Sepúlveda, Denisse; Rojas‐Rivera, Diego; Rodríguez, Diego A.; Groenendyk, Jody; Kohler, Andrés; Lebeaupin, Cynthia; Ito, Shinya; Urra, Hery; Carreras-Sureda, Amado; Hazari, Younis; Vasseur-Cognet, Mireille; Ali, Maruf M. U.; Chevet, Éric; Campos, Gisela; Godoy, Patrício; Vaisar, Tomáš; Bailly-Maître, Béatrice; Nagata, Kazuhiro; Michalak, Marek; Sierralta, Jimena; Hetz, Claudio

doi:10.1016/j.molcel.2017.12.028

Cited by 150 publications

(160 citation statements)

References 76 publications

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“…Further cell-based and structural studies are needed to define the IRE1β–IRE1α interaction and how distinct IRE1β/IRE1α assemblies confer preference for XBP1 cleavage versus RIDD activity. Likewise, other ER proteins (Amin-Wetzel et al, 2017; Bertolotti et al, 2000; Sepulveda et al, 2018; Sundaram et al, 2017) and mediators of apoptosis (Lisbona et al, 2009; Shemorry et al, 2019) also regulate IRE1α activity. How IRE1β affects these interactions and regulatory mechanisms also remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress

Grey

Cloots

Simpson

et al. 2020

Journal of Cell Biology

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IRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1β have an attenuated unfolded protein response to ER stress. When modeled in HEK293 cells and with purified protein, IRE1β diminishes expression and inhibits signaling by the closely related stress sensor IRE1α. IRE1β can assemble with and inhibit IRE1α to suppress stress-induced XBP1 splicing, a key mediator of the unfolded protein response. In comparison to IRE1α, IRE1β has relatively weak XBP1 splicing activity, largely explained by a nonconserved amino acid in the kinase domain active site that impairs its phosphorylation and restricts oligomerization. This enables IRE1β to act as a dominant-negative suppressor of IRE1α and affect how barrier epithelial cells manage the response to stress at the host–environment interface.

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Section: Discussionmentioning

confidence: 99%

IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress

Grey

Cloots

Simpson

et al. 2020

Journal of Cell Biology

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“…A FRET UPR induction assay, developed to quantify the association and dissociation of the IRE1 luminal domain from BiP upon ER stress , demonstrated that the ER luminal co‐chaperone ERdj4/DNAJB9 represses IRE1 by promoting a complex between BiP and the luminal stress‐sensing domain of IRE1α . Moreover, it has recently been reported that another ER luminal chaperone, Hsp47, displaces BiP from the IRE1 UPRosome to promote its oligomerization . Once released from BiP, IRE1 and PERK homodimerize or oligomerize and trans‐autophosphorylate to activate their downstream pathways .…”

Section: Er Stress Consequencesmentioning

confidence: 99%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

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“…Under these conditions, the transmembrane domain and the cytosolic effector domains ‘follow’ the oligomerization of the ER-luminal domains. A large diversity of ER-luminal and cytosolic interactors including chaperones can tune and specify the activity of mammalian UPR transducers (14, 48). This may reflect a way to custom-tailor the globally-acting UPR to different cell types with distinct protein folding requirements during steady-state and particularly during differentiation.…”

Section: Discussionmentioning

confidence: 99%

Cysteine crosslinking in native membranes establishes the transmembrane architecture of Ire1

Vaeth

Mattes

Reinhard

et al. 2019

Preprint

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36The endoplasmic reticulum (ER) is a key organelle of membrane biogenesis and 37 crucial for the folding of both membrane and secretory proteins. Stress sensors of the 38 unfolded protein response (UPR) monitor the unfolded protein load in the ER and 39 convey effector functions for the maintenance of ER homeostasis. More recently, it 40 became clear that aberrant compositions of the ER membrane, referred to as lipid 41 bilayer stress, are equally potent activators of the UPR with important implications in 42 obesity and diabetes. How the distinct signals from lipid bilayer stress and proteotoxic 43 stress are processed by the highly conserved UPR transducer Ire1 remains unknown. 44Here, we have generated a functional, cysteine-less variant of Ire1 and performed 45 systematic cysteine crosslinking experiments to establish the transmembrane 46 architecture of signaling-active clusters in native membranes. We show that the 47 transmembrane helices of two neighboring Ire1 molecules adopt an X-shaped 48 configuration and that this configuration is independent of the primary cause for ER 49 stress. Based on these findings, we propose that different forms of stress converge in 50 a single, signaling-active conformation of Ire1.

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Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α

Cited by 150 publications

References 76 publications

IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress

IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

Cysteine crosslinking in native membranes establishes the transmembrane architecture of Ire1

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