bims-ershed 2023-05-28 papers

iScience. 2023 May 19. 26(5): 106687

A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment.

Diana Pelizzari-Raymundo, Dimitrios Doultsinos, Raphael Pineau, Chloé Sauzay, Thodoris Koutsandreas, Timothy Langlais, Antonio Carlesso, Elena Gkotsi, Luc Negroni, Tony Avril, Aristotelis Chatziioannou, Eric Chevet, Leif A Eriksson, Xavier Guillory.

Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood-brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB.

Keywords: Biological sciences; Medicine; Molecular neuroscience; Neuroscience

DOI: https://doi.org/10.1016/j.isci.2023.106687

Cell Calcium. 2023 May 12. pii: S0143-4160(23)00065-9. [Epub ahead of print]113 102753

Interplay between calcium and endoplasmic reticulum stress.

Jody Groenendyk, Marek Michalak.

Cellular homeostasis is crucial for the healthy functioning of the organism. Disruption of cellular homeostasis activates endoplasmic reticulum (ER) stress coping responses including the unfolded protein response (UPR). There are three ER resident stress sensors responsible for UPR activation - IRE1α, PERK and ATF6. Ca2+ signaling plays an important role in stress responses including the UPR and the ER is the main Ca2+ storage organelle and a source of Ca2+ for cell signaling. The ER contains many proteins involved in Ca2+ import/export/ storage, Ca2+ movement between different cellular organelles and ER Ca2+ stores refilling. Here we focus on selected aspects of ER Ca2+ homeostasis and its role in activation of the ER stress coping responses.

Keywords: Calcium homeostasis; Endoplasmic reticulum; Membrane contact sites; Sarcoplasmic reticulum; Unfolded protein response

DOI: https://doi.org/10.1016/j.ceca.2023.102753

Mucosal Immunol. 2023 May 18. pii: S1933-0219(23)00038-7. [Epub ahead of print]

Unfolded Protein Response Factor ATF6 Augments T Helper Cell Responses and Promotes Mixed Granulocytic Airway Inflammation.

Dandan Wu, Xing Zhang, Kourtney M Zimmerly, Ruoning Wang, Chunqing Wang, Russell Hunter, Xiang Wu, Matthew Campen, Meilian Liu, Xuexian O Yang.

The unfolded protein response (UPR) is associated with the risk of asthma, including treatment-refractory severe asthma. Several recent studies demonstrated a pathogenic role of activating transcription factor 6α (ATF6α or ATF6), one of the essential arms of UPR, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by STAT6 and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine secretion of TH2 and TH17 cells. T cell-specificAtf6-deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed ATF6 downstream gene expression and TH cell cytokine expression in both murine and human memory CD4+ T cells. At the chronic stage of asthma, administration of Ceapin A7 lessened TH2 and TH17 responses in vivo, leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a critical role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma by targeting ATF6.

Keywords: ATF6; ER stress; TH17; TH2; mixed granulocytic asthma

DOI: https://doi.org/10.1016/j.mucimm.2023.05.007