bims-unfpre 2021-11-07 papers

Issue of 2021–11–07
six papers selected by
Susan Logue, University of Manitoba

Cell Death Dis. 2021 Nov 01. 12(11): 1038

PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells.

Namratha Sheshadri, Dipak K Poria, Shikha Sharan, Ying Hu, Chunhua Yan, Vishal N Koparde, Kuppusamy Balamurugan, Esta Sterneck.

Cancer cells experience endoplasmic reticulum (ER) stress due to activated oncogenes and conditions of nutrient deprivation and hypoxia. The ensuing unfolded protein response (UPR) is executed by ATF6, IRE1 and PERK pathways. Adaptation to mild ER stress promotes tumor cell survival and aggressiveness. Unmitigated ER stress, however, will result in cell death and is a potential avenue for cancer therapies. Because of this yin-yang nature of ER stress, it is imperative that we fully understand the mechanisms and dynamics of the UPR and its contribution to the complexity of tumor biology. The PERK pathway inhibits global protein synthesis while allowing translation of specific mRNAs, such as the ATF4 transcription factor. Using thapsigargin and tunicamycin to induce acute ER stress, we identified the transcription factor C/EBPδ (CEBPD) as a mediator of PERK signaling to secretion of tumor promoting chemokines. In melanoma and breast cancer cell lines, PERK mediated early induction of C/EBPδ through ATF4-independent pathways that involved at least in part Janus kinases and the STAT3 transcription factor. Transcriptional profiling revealed that C/EBPδ contributed to 20% of thapsigargin response genes including chaperones, components of ER-associated degradation, and apoptosis inhibitors. In addition, C/EBPδ supported the expression of the chemokines CXCL8 (IL-8) and CCL20, which are known for their tumor promoting and immunosuppressive properties. With a paradigm of short-term exposure to thapsigargin, which was sufficient to trigger prolonged activation of the UPR in cancer cells, we found that conditioned media from such cells induced cytokine expression in myeloid cells. In addition, activation of the CXCL8 receptor CXCR1 during thapsigargin exposure supported subsequent sphere formation by cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in tumor cells that may be particularly relevant in the context of pharmacological interventions.

DOI: https://doi.org/10.1038/s41419-021-04318-y

Mol Metab. 2021 Oct 30. pii: S2212-8778(21)00212-X. [Epub ahead of print] 101365

An accomplice more than a mere victim: the impact of β-cell ER stress on type 1 diabetes pathogenesis.

Gulcan Semra Sahin, Hugo Lee, Feyza Engin.

Pancreatic β-cells are the insulin factory of the organism with a mission to regulate glucose homeostasis in the body. Due to their high secretory activity, β-cells rely on a functional and intact endoplasmic reticulum (ER). Perturbations to ER homeostasis and unmitigated stress lead to β-cell dysfunction and death. Type 1 diabetes (T1D) is a chronic inflammatory disease caused by autoimmune-mediated destruction of β-cells. Although autoimmunity is an essential component of T1D pathogenesis, accumulating evidence suggests that β-cell ER stress and aberrant unfolded protein response (UPR) can play an important role in disease initiation and progression. Here, we review β-cell ER stress in various mouse models, evaluate its involvement in inflammation, and discuss the effects of ER stress on β-cell plasticity and demise, and islet autoimmunity in T1D. Finally, we provide insight into therapeutic targeting of ER stress and the UPR for prevention or treatment of T1D.

Keywords: NOD mice; beta cell; er stress; human islets; type 1 diabetes

DOI: https://doi.org/10.1016/j.molmet.2021.101365

Cancer Discov. 2021 Nov 05.

Tumor-Secreted Lipids Induce ER Stress Response to Polarize Macrophages.

Tumor-secreted lipids alter ER membrane composition to polarize tumor-associated macrophages (TAM).

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-160

Sci Rep. 2021 Nov 03. 11(1): 21584

Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF.

Susan Monkley, Catherine Overed-Sayer, Helen Parfrey, Doris Rassl, Damian Crowther, Leire Escudero-Ibarz, Nicola Davis, Alan Carruthers, Richard Berks, Marisa Coetzee, Ewa Kolosionek, Maria Karlsson, Leia R Griffin, Maryam Clausen, Graham Belfield, Cory M Hogaboam, Lynne A Murray.

The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-β-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.

DOI: https://doi.org/10.1038/s41598-021-00769-7

Mol Cancer Res. 2021 Nov 02. pii: molcanres.0702.2021. [Epub ahead of print]

PERK, Beyond an Unfolded Protein Response Sensor in Estrogen-induced Apoptosis in Endocrine-Resistant Breast Cancer.

Ping Fan, V Craig Jordan.

The discovery of 17β-estradiol (E2)-induced apoptosis has clinical relevance. Mechanistically, E2 over activates nuclear estrogen receptor α (ERα) that results in stress responses. The unfolded protein response (UPR) is initiated by E2 in the endoplasmic reticulum after hours of treatment in endocrine-resistant breast cancer cells, thereby activating three UPR sensors-PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) with different functions. Specifically, PERK plays a critical role in induction of apoptosis while IRE1α and ATF6 are involved in the endoplasmic reticulum stress-associated degradation (ERAD) of PI3K/Akt/mTOR pathways. In addition to attenuating protein translation, PERK increases the DNA-binding activity of nuclear factor-κB (NF-κB) and subsequent tumor necrosis factor α (TNFα) expression. Additionally, PERK communicates with the mitochondria to regulate oxidative stress at mitochondria-associated endoplasmic reticulum membranes (MAMs). Furthermore, PERK is a component enriched in MAMs that interacts with multifunctional MAM-tethering proteins and integrally modulates the exchange of metabolites such as lipids, reactive oxygen species (ROS), and Ca2+ at contact sites. MAMs are also critical sites for the initiation of autophagy to remove defective organelles and misfolded proteins through specific regulatory proteins. Thus, PERK conveys signals from nucleus to these membrane-structured organelles that form an interconnected network to regulate E2-induced apoptosis. Herein, we address the mechanistic progress on how PERK acts as a multifunctional molecule to commit E2 to inducing apoptosis in endocrine-resistant breast cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0702

Cell Death Dis. 2021 Nov 01. 12(11): 1040

CaMKK2 facilitates Golgi-associated vesicle trafficking to sustain cancer cell proliferation.

Lorna M Stewart, Lisa Gerner, Mandy Rettel, Frank Stein, James F Burrows, Ian G Mills, Emma Evergren.

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) regulates cell and whole-body metabolism and supports tumorigenesis. The cellular impacts of perturbing CAMKK2 expression are, however, not yet fully characterised. By knocking down CAMKK2 levels, we have identified a number of significant subcellular changes indicative of perturbations in vesicle trafficking within the endomembrane compartment. To determine how they might contribute to effects on cell proliferation, we have used proteomics to identify Gemin4 as a direct interactor, capable of binding CAMKK2 and COPI subunits. Prompted by this, we confirmed that CAMKK2 knockdown leads to concomitant and significant reductions in δ-COP protein. Using imaging, we show that CAMKK2 knockdown leads to Golgi expansion, the induction of ER stress, abortive autophagy and impaired lysosomal acidification. All are phenotypes of COPI depletion. Based on our findings, we hypothesise that CAMKK2 sustains cell proliferation in large part through effects on organelle integrity and membrane trafficking.

DOI: https://doi.org/10.1038/s41419-021-04335-x