bims-unfpre 2022-11-27 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–11–27
seven papers selected by
Susan Logue, University of Manitoba

Brain injury triggers cell-type-specific and time-dependent endoplasmic reticulum stress responses.
Unfolded protein response and angiogenesis in malignancies.
ER stress as a trigger of UPR and ER-phagy in cancer growth and spread.
Major histocompatibility complex I-induced endoplasmic reticulum stress mediates the secretion of pro-inflammatory muscle-derived cytokines.
Role of endoplasmic reticulum stress and autophagy in the transition from acute kidney injury to chronic kidney disease.
Activating transcription factor 4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells.
Mast cells inhibit colorectal cancer development by inducing ER stress through secreting Cystatin C.

Glia. 2022 Nov 22.

Brain injury triggers cell-type-specific and time-dependent endoplasmic reticulum stress responses.

Qiyan Fan, Mika Takarada-Iemata, Nahoko Okitani, Takashi Tamatani, Hiroshi Ishii, Tsuyoshi Hattori, Sumiko Kiryu-Seo, Hiroshi Kiyama, Osamu Hori.

  The unfolded protein response (UPR) is a signal transduction network that responds to endoplasmic reticulum (ER) stress by coordinating protein homeostasis to maintain cell viability. The UPR can also trigger cell death when adaptive responses fail to improve protein homeostasis. Despite accumulating evidence suggesting that the UPR plays a role in neurodegenerative diseases and brain insults, our understanding of how ER stress is induced under neuropathological conditions is limited. Here, we investigated the cell- and time-specific patterns of the ER stress response after brain injury using ER stress-activated indicator (ERAI) mice, which enable monitoring of the UPR in vivo via increased fluorescence of a spliced XBP-1 protein fused with the green fluorescent protein (GFP) variant Venus. Following cortical stab injury of ERAI mice, the GFP signal and number of GFP+ cells increased in the ipsilateral cortex throughout the observation period (6 h to 7 days post-injury), confirming the induction of the UPR. GFP signals were observed in injured neurons early (from 6 h) after brain injury. However, non-neuronal cells, mainly endothelial cells followed by astrocytes, accounted for the majority of GFP+ cells after brain injury. Similar results were obtained in a mouse model of focal cerebral ischemia. These findings suggest that activation of the UPR in both neuronal and non-neuronal cells, especially endothelial cells and astrocytes, may play an important role in and could be a potential therapeutic target for acute brain injuries.

Keywords:  ER stress; ERAI; UPR; astrocytes; brain injury; cerebral ischemia; endothelial cells

DOI:  https://doi.org/10.1002/glia.24303
Biochim Biophys Acta Rev Cancer. 2022 Nov 19. pii: S0304-419X(22)00164-0. [Epub ahead of print] 188839

Unfolded protein response and angiogenesis in malignancies.

Amin Izadpanah, Kurtis Willingham, Bysani Chandrasekar, Eckhard U Alt, Reza Izadpanah.

  Cellular stress, arising from accumulation of unfolded proteins, occurs frequently in rapidly proliferating cancer cells. This cellular stress, in turn, activates the unfolded protein response (UPR), an interconnected set of signal transduction pathways that alleviate the proteostatic stress. The UPR is implicated in cancer cell survival and proliferation through upregulation of pro-tumorigenic pathways that ultimately promote malignant metabolism and neoangiogenesis. Here, we reviewed mechanisms of signaling crosstalk between the UPR and angiogenesis pathways, as well as transmissible ER stress and the role in tumor growth and development. To characterize differences in UPR and UPR-mediated angiogenesis in malignancy, we employed a data mining approach using patient tumor data from The Cancer Genome Atlas (TCGA). The analysis of TCGA revealed differences in UPR between malignant samples versus their non-malignant counterparts.

Keywords:  ATF6; IRE1α; PERK; Tumor microenvironment; Unfolded protein response; XBP1

DOI:  https://doi.org/10.1016/j.bbcan.2022.188839
Front Oncol. 2022 ;12 997235

ER stress as a trigger of UPR and ER-phagy in cancer growth and spread.

Alessandro Cherubini, Ester Zito.

  Tumors can survive environmental and metabolic stress by triggering homeostatic responses that re-establish the pre-stress status and permit them to grow and thrive. The endoplasmic reticulum (ER) is the organelle where proteins undergo post-translational modifications and are folded and exported to the secretory pathway. Its environment and activity are therefore fundamental for proteostasis, i.e., the plethora of mechanisms controlling protein formation, folding, degradation, and secretion, needed to assure protein balance and cellular health. In different tumor-related conditions, such as after the activation of oncogenes or under hypoxia and nutrient deprivation, the ER experiences stress, triggered by a high load of proteins to be folded compared to the limited folding capacity of the organelle. As a consequence, three ER membrane sensors and the related unfolded protein response (UPR) are activated. The UPR comprises a complex interconnection between signal transduction pathways that promote a homeostatic response that acts by increasing the amount of protein chaperones and of proteins involved in ER-associated protein degradation (ERAD) on one hand and attenuating protein translation on the other. ER-phagy, literally "eating" the ER, is part of another homeostatic response consisting of the clearance of non-functional ER portions including misfolded proteins. This response is also activated by a set of dedicated ER-phagy receptors after ER stimuli, which overlap the stimuli generating ER stress. Thus, the UPR and ER-phagy are two closely related homeostatic mechanisms that cooperate in re-establishing ER homeostasis. However, while the role of the UPR in favoring cancer growth and thriving by promoting angiogenesis, metastasis, chemotherapy resistance, and epithelial-to-mesenchymal transition is consolidated, that of ER-phagy is still in its infancy. This essay provides an overview of emerging concepts on ER stress, the UPR, and ER-phagy and their crosstalk in tumorigenesis. We also critically review new findings on their pharmacological targeting in cancer.

Keywords:  ER stress; ER-phagy; ERO1 alpha; UPR; cancer; hypoxia

DOI:  https://doi.org/10.3389/fonc.2022.997235
J Cell Mol Med. 2022 Nov 25.

Major histocompatibility complex I-induced endoplasmic reticulum stress mediates the secretion of pro-inflammatory muscle-derived cytokines.

Anastasia Thoma, Kate E Earl, Katarzyna Goljanek-Whysall, Adam P Lightfoot.

  Major histocompatibility complex (MHC) I is an important component of intracellular antigen presentation. However, improper expression of MHC I upon the cell surface has been associated with several autoimmune diseases. Myositis is a rare acquired autoimmune disease which targets skeletal muscle, and MHC I overexpression on the surface of muscle fibres and immune cell infiltration are clinical hallmarks. MHC I overexpression may have an important pathogenic role, mediated by the activation of the endoplasmic reticulum (ER) stress response. Given the evidence that muscle is a diverse source of cytokines, we aimed to investigate whether MHC I overexpression can modify the profile of muscle-derived cytokines and what role the ER stress pathway may play. Using C2C12 myoblasts we overexpressed MHC I with a H-2kb vector in the presence or absence of salubrinal an ER stress pathway modifying compound. MHC I overexpression induced ER stress pathway activation and elevated cytokine gene expression. MHC I overexpression caused significant release of cytokines and chemokines, which was attenuated in the presence of salubrinal. Conditioned media from MHC I overexpressing cells induced in vitro T-cell chemotaxis, atrophy of healthy myotubes and modified mitochondrial function, features which were attenuated in the presence of salubrinal. Collectively, these data suggest that MHC I overexpression can induce pro-inflammatory cytokine/chemokine release from C2C12 myoblasts, a process which appears to be mediated in-part by the ER stress pathway.

Keywords:  ER stress; major histocompatibility complex (MHC) I; myokines; skeletal muscle

DOI:  https://doi.org/10.1111/jcmm.17621
J Cell Physiol. 2022 Nov 21.

Role of endoplasmic reticulum stress and autophagy in the transition from acute kidney injury to chronic kidney disease.

Tahib Habshi, Vishwadeep Shelke, Ajinath Kale, Hans-Joachim Anders, Anil Bhanudas Gaikwad.

  Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health concerns with increasing rates in morbidity and mortality. Transition from AKI-to-CKD is common and requires awareness in the management of AKI survivors. AKI-to-CKD transition is a main risk factor for the development of cardiovascular disease and progression to end-stage kidney disease. The mechanisms driving AKI-to-CKD transition are being explored to identify potential molecular and cellular targets for renoprotective drug interventions. Endoplasmic reticulum (ER) stress and autophagy are involved in the process of AKI-to-CKD transition. Excessive ER stress results in the persistent activation of unfolded protein response, which is an underneath cause of kidney cell death. Moreover, ER stress modulates autophagy and vice-versa. Autophagy is a degradation defensive mechanism protecting cells from malfunction. However, the underlying pathological mechanism involved in this interplay in the context of AKI-to-CKD transition is still unclear. In this review, we discuss the crosstalk between ER stress and autophagy in AKI, AKI-to-CKD transition, and CKD progression. In addition, we explore possible therapeutic targets that can regulate ER stress and autophagy to prevent AKI-to-CKD transition to improve the long-term prognosis of AKI survivors.

Keywords:  AKI-to-CKD transition; ER stress; acute kidney injury; autophagy; chronic kidney disease

DOI:  https://doi.org/10.1002/jcp.30918
Oncol Rep. 2023 Jan;pii: 14. [Epub ahead of print]49(1):

Activating transcription factor 4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells.

Nancy T Chee, Candace H Carriere, Zachary Miller, Scott Welford, Shaun P Brothers.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and difficult to treat cancers with tumors typically exhibiting high levels of chronic hypoxia. Hypoxia activates hypoxia-inducible factors (HIFs) that mediate cellular responses to adapt to low oxygen environments. Hypoxia also causes endoplasmic reticulum (ER) stress, increasing activating transcription factor 4 (ATF4), a master regulator of the unfolded protein response (UPR) pathway that mediates cellular response to ER stress. ATF4 is overexpressed in PDAC and is associated with poor prognoses. While ATF4 promotes cell proliferation and tumorigenesis, most studies have been conducted under normoxia or acute hypoxia. The functions of ATF4 in chronic hypoxia remain largely unexplored. Using siRNA knockdown experiments of healthy skin fibroblast cells WS1 and PDAC cell lines PANC-1 and Mia-PaCa2 to analyze mRNA and protein expression levels, a novel ATF4 function was identified, in which it decreases HIF2α mRNA and increases HIF1α mRNA in chronic hypoxia while having no effect in acute hypoxia. A scratch assay was used to show that ATF4 decreases cell migration in chronic hypoxia as opposed to the increase in cell migration ATF4 imparts in acute hypoxia. Colony formation assay and cell viability assay showed that ATF4 promotes colony formation and cell viability in both chronic and acute hypoxia. In addition to the differential response of ATF4 in chronic hypoxia compared with acute hypoxia, this is the first time ATF4 has been implicated in regulation of response to hypoxia via interaction with HIF proteins in PDAC.

Keywords:  ATF4; HIF1α; HIF2α; PDAC; UPR pathway; chronic hypoxia

DOI:  https://doi.org/10.3892/or.2022.8451
Oncogene. 2022 Nov 19.

Mast cells inhibit colorectal cancer development by inducing ER stress through secreting Cystatin C.

Feifei Song, Youhua Zhang, Qi Chen, Dexi Bi, Muqing Yang, Ling Lu, Man Li, Huiyuan Zhu, Ying Liu, Qing Wei, Huanlong Qin, Jiyu Li.

Mast cells (MCs) are abundantly distributed in the human intestinal mucosa and submucosa. However, their roles and mechanisms in the development of colorectal cancer (CRC) are still unclear. In the present research, we found that the infiltration density of MCs in CRC tissues was positively correlated with improved patients' prognoses. Moreover, MCs suppressed the growth and induced the apoptosis of CRC cells in vitro and in vivo but had no effect on normal colonic epithelial cells. The present study revealed that MCs specifically induced endoplasmic reticulum stress (ERS) and activated the unfolded protein response (UPR) in CRC cells but not in normal cells, which led to the suppression of CRC development in vivo. Furthermore, we found that the secreted Cystatin C protein was the key factor for the MC-induced ERS in CRC cells. This work is of significance for uncovering the antitumor function of MCs in CRC progression and identifying the potential of CRC to respond to MC-targeted immunotherapy.

DOI: https://doi.org/10.1038/s41388-022-02543-z