bims-unfpre 2019-05-19 papers

Issue of 2019–05–19
five papers selected by
Susan Logue, University of Manitoba

Nat Immunol. 2019 May 13.

The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc.

Han Dong, Nicholas M Adams, Yichi Xu, Jin Cao, David S J Allan, James R Carlyle, Xi Chen, Joseph C Sun, Laurie H Glimcher.

Natural killer (NK) cells are critical mediators of host immunity to pathogens. Here, we demonstrate that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mammalian target of rapamycin signaling pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1α downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1α-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1α-/- NK cells. Like c-Myc, IRE1α-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1α-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer.

DOI: https://doi.org/10.1038/s41590-019-0388-z

Front Cell Dev Biol. 2019 ;7 66

CD90/Thy-1, a Cancer-Associated Cell Surface Signaling Molecule.

Chloé Sauzay, Konstantinos Voutetakis, Aristotelis Chatziioannou, Eric Chevet, Tony Avril.

CD90 is a membrane GPI-anchored protein with one Ig V-type superfamily domain that was initially described in mouse T cells. Besides the specific expression pattern and functions of CD90 that were described in normal tissues, i.e., neurons, fibroblasts and T cells, increasing evidences are currently highlighting the possible involvement of CD90 in cancer. This review first provides a brief overview on CD90 gene, mRNA and protein features and then describes the established links between CD90 and cancer. Finally, we report newly uncovered functional connections between CD90 and endoplasmic reticulum (ER) stress signaling and discuss their potential impact on cancer development.

Keywords: CD90; ER stress; IRE1; THY-1; cancer; invasion; migration

DOI: https://doi.org/10.3389/fcell.2019.00066

Trends Mol Med. 2019 May 08. pii: S1471-4914(19)30066-8. [Epub ahead of print]

Proteostasis and Beyond: ATF6 in Ischemic Disease.

Christopher C Glembotski, Jessica D Rosarda, R Luke Wiseman.

Endoplasmic reticulum (ER) stress is a pathological hallmark of numerous ischemic diseases, including stroke and myocardial infarction (MI). In these diseases, ER stress leads to activation of the unfolded protein response (UPR) and subsequent adaptation of cellular physiology in ways that dictate cellular fate following ischemia. Recent evidence highlights a protective role for the activating transcription factor 6 (ATF6) arm of the UPR in mitigating adverse outcomes associated with ischemia/reperfusion (I/R) injury in multiple disease models. This suggests ATF6 as a potential therapeutic target for intervening in diverse ischemia-related disorders. Here, we discuss the evidence demonstrating the importance of ATF6 signaling in protecting different tissues against ischemic damage and discuss preclinical results focused on defining the potential for pharmacologically targeting ATF6 to intervene in such diseases.

Keywords: ATF6; ER stress; myocardial infarction; stroke; unfolded protein response

DOI: https://doi.org/10.1016/j.molmed.2019.03.005

Proc Natl Acad Sci U S A. 2019 May 17. pii: 201904516. [Epub ahead of print]

Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress.

Aeid Igbaria, Philip I Merksamer, Ala Trusina, Firehiwot Tilahun, Jeffrey R Johnson, Onn Brandman, Nevan J Krogan, Jonathan S Weissman, Feroz R Papa.

Diverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such "ER stress," we employed an ER-targeted, redox-responsive, green fluorescent protein-eroGFP-that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress regimes cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to "reflux" back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in Saccharomyces cerevisiae, we show that ER protein reflux during ER stress requires specific chaperones and cochaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.

Keywords: ERAD; UPR; endoplasmic reticulum stress; reflux

DOI: https://doi.org/10.1073/pnas.1904516116

Nat Commun. 2019 05 13. 10(1): 2139

An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy.

Cedric Darini, Nour Ghaddar, Catherine Chabot, Gloria Assaker, Siham Sabri, Shuo Wang, Jothilatha Krishnamoorthy, Marguerite Buchanan, Adriana Aguilar-Mahecha, Bassam Abdulkarim, Jean Deschenes, Jose Torres, Josie Ursini-Siegel, Mark Basik, Antonis E Koromilas.

Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21CIP1 and activates JNK1/2. The PKR/eIF2α-P arm is induced by Trastuzumab in sensitive but not resistant HER2+ breast tumors. Also, eIF2α-P stimulation by the phosphatase inhibitor SAL003 substantially increases Trastuzumab potency in resistant HER2+ breast and gastric tumors. Increased eIF2α-P prognosticates a better response of HER2+ metastatic breast cancer patients to Trastuzumab therapy. Hence, the PKR/eIF2α-P arm antagonizes HER2 tumorigenesis whereas its pharmacological stimulation improves the efficacy of Trastuzumab therapy.

DOI: https://doi.org/10.1038/s41467-019-10138-8