bims-unfpre 2024-07-07 papers

Issue of 2024–07–07
five papers selected by
Susan Logue, University of Manitoba

Front Pharmacol. 2024 ;15 1419468

Endoplasmic reticulum stress and quality control in relation to cisplatin resistance in tumor cells.

Wentao Mu, Yao Zhi, Jianpeng Zhou, Chuanlei Wang, Kaiyuan Chai, Zhongqi Fan, Guoyue Lv.

The endoplasmic reticulum (ER) is a crucial organelle that orchestrates key cellular functions like protein folding and lipid biosynthesis. However, it is highly sensitive to disturbances that lead to ER stress. In response, the unfolded protein response (UPR) activates to restore ER homeostasis, primarily through three sensors: IRE1, ATF6, and PERK. ERAD and autophagy are crucial in mitigating ER stress, yet their dysregulation can lead to the accumulation of misfolded proteins. Cisplatin, a commonly used chemotherapy drug, induces ER stress in tumor cells, activating complex signaling pathways. Resistance to cisplatin stems from reduced drug accumulation, activation of DNA repair, and anti-apoptotic mechanisms. Notably, cisplatin-induced ER stress can dualistically affect tumor cells, promoting either survival or apoptosis, depending on the context. ERAD is crucial for degrading misfolded proteins, whereas autophagy can protect cells from apoptosis or enhance ER stress-induced apoptosis. The complex interaction between ER stress, cisplatin resistance, ERAD, and autophagy opens new avenues for cancer treatment. Understanding these processes could lead to innovative strategies that overcome chemoresistance, potentially improving outcomes of cisplatin-based cancer treatments. This comprehensive review provides a multifaceted perspective on the complex mechanisms of ER stress, cisplatin resistance, and their implications in cancer therapy.

Keywords: ER-phagy; ERAD; chemoresistance; cisplatin; endoplasmic reticulum; er stress

DOI: https://doi.org/10.3389/fphar.2024.1419468

Cell Rep. 2024 Jun 27. pii: S2211-1247(24)00730-7. [Epub ahead of print]43(7): 114402

Translocational attenuation mediated by the PERK-SRP14 axis is a protective mechanism of unfolded protein response.

Yaofu Liu, Yuexi Gu, Ying Chen, Xuan Wang, Guangfeng Zhou, Jing Li, Mu Wang, Shengyun Fang, Yili Yang.

The unfolded protein response (UPR) relieves endoplasmic reticulum (ER) stress through multiple strategies, including reducing protein synthesis, increasing protein folding capabilities, and enhancing misfolded protein degradation. After a multi-omics analysis, we find that signal recognition particle 14 (SRP14), an essential component of the SRP, is markedly reduced in cells undergoing ER stress. Further experiments indicate that SRP14 reduction requires PRKR-like ER kinase (PERK)-mediated eukaryotic translation initiation factor 2α (eIF2α) phosphorylation but is independent of ATF4 or ATF3 transcription factors. The decrease of SRP14 correlates with reduced translocation of fusion proteins and endogenous cathepsin D. Enforced expression of an SRP14 variant with elongation arrest capability prevents the reduced translocation of cathepsin D in stressed cells, whereas an SRP14 mutant without the activity does not. Finally, overexpression of SRP14 augments the UPR and aggravates ER-stress-induced cell death. These data suggest that translocational attenuation mediated by the PERK-SRP14 axis is a protective measure for the UPR to mitigate ER stress.

Keywords: CP: Molecular biology; ER stress; PERK-eIF2α; SRP14; UPR; cathepsin D; signal peptide; signal recognition particle; translocational attenuation

DOI: https://doi.org/10.1016/j.celrep.2024.114402

Sci Rep. 2024 07 01. 14(1): 14990

sUPRa is a dual-color reporter for unbiased quantification of the unfolded protein response with cellular resolution.

Atreyi Chakrabarty, Sarah E Newey, Maisha M Promi, Belinda K Agbetiameh, Daniella Munro, Paul J N Brodersen, Gemma Gothard, Kashif Mahfooz, Jose P Mengual, Vladyslav V Vyazovskiy, Colin J Akerman.

The unfolded protein response (UPR) maintains proteostasis upon endoplasmic reticulum (ER) stress, and is initiated by a range of physiological and pathological processes. While there have been advances in developing fluorescent reporters for monitoring individual signaling pathways of the UPR, this approach may not capture a cell's overall UPR activity. Here we describe a novel sensor of UPR activity, sUPRa, which is designed to report the global UPR. sUPRa displays excellent response characteristics, outperforms reporters of individual UPR pathways in terms of sensitivity and kinetics, and responds to a range of different ER stress stimuli. Furthermore, sUPRa's dual promoter and fluorescent protein design ensures that both UPR-active and inactive cells are detected, and controls for reporter copy number. Using sUPRa, we reveal UPR activation in layer 2/3 pyramidal neurons of mouse cerebral cortex following a period of sleep deprivation. sUPRa affords new opportunities for quantifying physiological UPR activity with cellular resolution.

DOI: https://doi.org/10.1038/s41598-024-65611-2

J Clin Invest. 2024 Jul 01. pii: e182204. [Epub ahead of print]134(13):

A little ER stress isn't bad: the IRE1α/XBP1 pathway shapes ILC3 functions during intestinal inflammation.

Cinzia Fionda, Giuseppe Sciumè.

Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.

DOI: https://doi.org/10.1172/JCI182204

Immun Inflamm Dis. 2024 Jul;12(7): e1301

X-Box binding protein 1 downregulates SIRT6 to promote injury in pancreatic ductal epithelial cells.

Zhuo Yang, Shaojun Li, Chuan Zhao, Zongzheng Zhao, Juan Tan, Lu Zhang, Yuanqing Huang.

OBJECTIVE: Acute pancreatitis (AP) stands as a frequent cause for clinical emergency hospital admissions. The X-box binding protein 1 (XBP1) was found to be implicated in pancreatic acinar cell apoptosis. The objective is to unveil the potential mechanisms governed by XBP1 and SIRT6 in the context of AP.
METHODS: Caerulein-treated human pancreatic duct epithelial (HPDE) cells to establish an in vitro research model. The levels and regulatory role of SIRT6 in the treated cells were evaluated, including its effects on inflammatory responses, oxidative stress, apoptosis, and endoplasmic reticulum stress. The relationship between XBP1 and SIRT6 was explored by luciferase and ChIP experiments. Furthermore, the effect of XBP1 overexpression on the regulatory function of SIRT6 on cells was evaluated.
RESULTS: Caerulein promoted the decrease of SIRT6 and the increase of XBP1 in HPDE cells. Overexpression of SIRT6 slowed down the secretion of inflammatory factors, oxidative stress, apoptosis level, and endoplasmic reticulum stress in HPDE cells. However, XBP1 negatively regulated SIRT6, and XBP1 overexpression partially reversed the regulation of SIRT6 on the above aspects.
CONCLUSION: Our study illuminates the role of XBP1 in downregulating SIRT6 in HPDE cells, thereby promoting cellular injury. Inhibiting XBP1 or augmenting SIRT6 levels holds promise in preserving cell function and represents a potential therapeutic avenue in the management of AP.

Keywords: ER stress; pancreatitis; pathology; sirtuin; transcription

DOI: https://doi.org/10.1002/iid3.1301