bims-unfpre 2021-10-31 papers

Issue of 2021–10–31
five papers selected by
Susan Logue, University of Manitoba

EMBO Rep. 2021 Oct 26. e52509

The unfolded protein response links tumor aneuploidy to local immune dysregulation.

Su Xian, Magalie Dosset, Gonzalo Almanza, Stephen Searles, Paras Sahani, T Cameron Waller, Kristen Jepsen, Hannah Carter, Maurizio Zanetti.

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here, we tested the hypothesis that the unfolded protein response (UPR) mechanistically links aneuploidy and local immune dysregulation. Using a single somatic copy number alteration (SCNA) score inclusive of whole-chromosome, chromosome arm, and focal alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups. Pathway activity scores showed increased activity of multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and arginase 1 transcription in receiver bone marrow-derived macrophages and markedly diminished the production of IFN-γ and granzyme B in activated human T cells. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment.

Keywords: T cells; aneuploidy; macrophages; tumor immune microenvironment; unfolded protein response

DOI: https://doi.org/10.15252/embr.202152509

Nat Rev Drug Discov. 2021 Oct 26.

Pharmacological targeting of endoplasmic reticulum stress in disease.

Stefan J Marciniak, Joseph E Chambers, David Ron.

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, resulting in activation of the unfolded protein response (UPR) that aims to restore protein homeostasis. However, the UPR also plays an important pathological role in many diseases, including metabolic disorders, cancer and neurological disorders. Over the last decade, significant effort has been invested in targeting signalling proteins involved in the UPR and an array of drug-like molecules is now available. However, these molecules have limitations, the understanding of which is crucial for their development into therapies. Here, we critically review the existing ER stress and UPR-directed drug-like molecules, highlighting both their value and their limitations.

DOI: https://doi.org/10.1038/s41573-021-00320-3

Diabetes. 2021 Nov;70(11): 2431-2443

Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells.

Rohit B Sharma, Huguet V Landa-Galván, Laura C Alonso.

Type 2 diabetes (T2D) is a growing cause of poor health, psychosocial burden, and economic costs worldwide. The pancreatic β-cell is a cornerstone of metabolic physiology. Insulin deficiency leads to hyperglycemia, which was fatal before the availability of therapeutic insulins; even partial deficiency of insulin leads to diabetes in the context of insulin resistance. Comprising only an estimated 1 g or <1/500th of a percent of the human body mass, pancreatic β-cells of the islets of Langerhans are a vulnerable link in metabolism. Proinsulin production constitutes a major load on β-cell endoplasmic reticulum (ER), and decompensated ER stress is a cause of β-cell failure and loss in both type 1 diabetes (T1D) and T2D. The unfolded protein response (UPR), the principal ER stress response system, is critical for maintenance of β-cell health. Successful UPR guides expansion of ER protein folding capacity and increased β-cell number through survival pathways and cell replication. However, in some cases the ER stress response can cause collateral β-cell damage and may even contribute to diabetes pathogenesis. Here we review the known beneficial and harmful effects of UPR pathways in pancreatic β-cells. Improved understanding of this stress response tipping point may lead to approaches to maintain β-cell health and function.

DOI: https://doi.org/10.2337/dbi20-0033

Cell Death Dis. 2021 Oct 29. 12(11): 1016

Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis.

Shaoqun Shu, Hui Wang, Jiefu Zhu, Zhiwen Liu, Danyi Yang, Wenwen Wu, Juan Cai, Anqun Chen, Chengyuan Tang, Zheng Dong.

Both endoplasmic reticulum (ER) stress and autophagy have been implicated in chronic kidney injury and renal fibrosis. However, the relationship and regulatory mechanisms between ER stress and autophagy under this condition remain largely unknown. In this study, we first established a mouse model of ER stress-induced chronic kidney injury by 2 weekly injections of a low dose of tunicamycin (TM), a classical ER stress inducer. This model showed the induction of ER stress, autophagy, fibrosis and apoptosis in kidney tissues. In vitro, TM also induced ER stress, autophagy, fibrosis and apoptosis in HK-2 human kidney proximal tubular cells and BUMPT-306 mouse kidney proximal tubular cells. In these cells, autophagy inhibitor suppressed TM-induced fibrotic changes and apoptosis, suggesting an involvement of autophagy in ER stress-associated chronic kidney injury. PERK inhibitor ameliorated autophagy, fibrotic protein expression and apoptosis in TM-treated cells, indicating a role of the PERK/eIF2α pathway in autophagy activation during ER stress. Similar results were shown in TGF-β1-treated HK-2 cells. Interestingly, in both TM- or TGF-β1-treated kidney proximal tubular cells, inhibition of autophagy exaggerated ER stress, suggesting that autophagy induced by ER stress provides a negative feedback mechanism to reduce the stress. Together, these results unveil a reciprocal regulation between ER stress and autophagy in chronic kidney injury and fibrosis.

DOI: https://doi.org/10.1038/s41419-021-04274-7

Cell Death Dis. 2021 Oct 26. 12(11): 1003

Cardiac-specific CGI-58 deficiency activates the ER stress pathway to promote heart failure in mice.

Xin Xie, Yi-Fan Tie, Song Lai, Yun-Long Zhang, Hui-Hua Li, Ying Liu.

Excess myocardial triacylglycerol accumulation (i.e., cardiac steatosis) impairs heart function, suggesting that enzymes promoting triacylglycerol metabolism exert essential regulatory effects on heart function. Comparative gene identification 58 (CGI-58) is a key enzyme that promotes the hydrolysis of triglycerides by activating adipose triglyceride lipase and plays a protective role in maintaining heart function. In this study, the effects of CGI-58 on heart function and the underlying mechanism were investigated using cardiac-specific CGI58-knockout mice (CGI-58cko mice). Echocardiography and pathological staining were performed to detect changes in the structure and function of the heart. Proteomic profiling, immunofluorescent staining, western blotting, and real-time PCR were used to evaluate molecular changes. In CGI-58cko mice, we detected cardiac hypertrophic remodeling and heart failure associated with excessive cardiac lipid accumulation, ROS production, and decreased expression of regulators of fatty acid metabolism. These changes were markedly attenuated in CGI-58cko mice injected with rAAV9-CGI58. A quantitative proteomics analysis revealed significant increases in the expression of ER stress-related proteins and decreases in proteins related to fatty acid and amino acid metabolism in the hearts of CGI-58cko mice. Furthermore, the inhibition of ER stress by the inhibitor 4-PBA improved mitochondrial dysfunction, reduced oxidative stress, and reversed cardiac remodeling and dysfunction in cultured cardiomyocytes or in CGI-58cko mice. Our results suggested that CGI-58 is essential for the maintenance of heart function by reducing lipid accumulation and ER stress in cardiomyocytes, providing a new therapeutic target for cardiac steatosis and dysfunction.

DOI: https://doi.org/10.1038/s41419-021-04282-7