bims-unfpre 2022-01-23 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–01–23
eight papers selected by
Susan Logue, University of Manitoba

Role of systems biology and multi-omics analyses in delineating spatial interconnectivity and temporal dynamicity of ER stress mediated cellular responses.
Endoplasmic Reticulum Stress and Unfolded Protein Response Signaling in Plants.
Inositol Requiring Enzyme (IRE), a multiplayer in sensing endoplasmic reticulum stress.
Impact of ER Stress and ER-Mitochondrial Crosstalk in Huntington's Disease.
Immunosuppressive calcineurin inhibitor cyclosporine A induces pro-apoptotic endoplasmic reticulum stress in renal tubular cells.
ER reductive stress caused by Ero1α S-nitrosation accelerates senescence.
PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes.
Targeting squalene epoxidase interrupts homologous recombination via the ER stress response and promotes radiotherapy efficacy.

Biochim Biophys Acta Mol Cell Res. 2022 Jan 12. pii: S0167-4889(22)00001-5. [Epub ahead of print] 119210

Role of systems biology and multi-omics analyses in delineating spatial interconnectivity and temporal dynamicity of ER stress mediated cellular responses.

Priyanka Mallick, Sebabrata Maity, Oishee Chakrabarti, Saikat Chakrabarti.

  The endoplasmic reticulum (ER) is a membranous organelle involved in calcium storage, lipid biosynthesis, protein folding and processing. Many patho-physiological conditions and pharmacological agents are known to perturb normal ER function and can lead to ER stress, which severely compromise protein folding mechanism and hence poses high risk of proteotoxicity. Upon sensing ER stress, the different stress signaling pathways interconnect with each other and work together to preserve cellular homeostasis. ER stress response is a part of the integrative stress response (ISR) and might play an important role in the pathogenesis of chronic neurodegenerative diseases, where misfolded protein accumulation and cell death are common. The initiation, manifestation and progression of ER stress mediated unfolded protein response (UPR) is a complex procedure involving multiple proteins, pathways and cellular organelles. To understand the cause and consequences of such complex processes, implementation of an integrative holistic approach is required to identify novel players and regulators of ER stress. As multi-omics data-based systems analyses have shown potential to unravel the underneath molecular mechanism of complex biological systems, it is important to emphasize the utility of this approach in understanding the ER stress biology. In this review we first discuss the ER stress signaling pathways and regulatory players, along with their inter-connectivity. We next highlight the importance of systems and network biology approaches using multi-omics data in understanding ER stress mediated cellular responses. This report would help advance our current understanding of the multivariate spatial interconnectivity and temporal dynamicity of ER stress.

Keywords:  Endoplasmic reticulum stress; Multi-omics approaches; Stress sensing pathways; Unfolded protein response; meta-pathway network

DOI:  https://doi.org/10.1016/j.bbamcr.2022.119210
Int J Mol Sci. 2022 Jan 13. pii: 828. [Epub ahead of print]23(2):

Endoplasmic Reticulum Stress and Unfolded Protein Response Signaling in Plants.

Hakim Manghwar, Jianming Li.

  Plants are sensitive to a variety of stresses that cause various diseases throughout their life cycle. However, they have the ability to cope with these stresses using different defense mechanisms. The endoplasmic reticulum (ER) is an important subcellular organelle, primarily recognized as a checkpoint for protein folding. It plays an essential role in ensuring the proper folding and maturation of newly secreted and transmembrane proteins. Different processes are activated when around one-third of newly synthesized proteins enter the ER in the eukaryote cells, such as glycosylation, folding, and/or the assembling of these proteins into protein complexes. However, protein folding in the ER is an error-prone process whereby various stresses easily interfere, leading to the accumulation of unfolded/misfolded proteins and causing ER stress. The unfolded protein response (UPR) is a process that involves sensing ER stress. Many strategies have been developed to reduce ER stress, such as UPR, ER-associated degradation (ERAD), and autophagy. Here, we discuss the ER, ER stress, UPR signaling and various strategies for reducing ER stress in plants. In addition, the UPR signaling in plant development and different stresses have been discussed.

Keywords:  ER; ER stress; IRE1; UPR; bZIP17; bZIP28; bZIP60; plants

DOI:  https://doi.org/10.3390/ijms23020828
Anim Cells Syst (Seoul). 2021 ;25(6): 347-357

Inositol Requiring Enzyme (IRE), a multiplayer in sensing endoplasmic reticulum stress.

Zhixin Zhou, Qian Wang, Marek Michalak.

  The endoplasmic reticulum (ER) can sense a wide variety of external and internal perturbations and responds by mounting stress coping responses, such as the unfolded protein response (UPR). The UPR is composed of three stress sensors, namely IRE1α, PERK, and ATF6 that are activated to re-establish ER homeostasis. IRE1α represents the most ancient branch of the UPR affecting many cellular processes in plant and animal cells. IRE1α is a type I transmembrane protein with kinase/nuclease activities in response to ER stress. Both the ER luminal and cytosolic IRE1α interactomes have been identified revealing a multifunctional role of the ER stress sensor. IRE1α is also associated with organellar membrane contacts to promote rapid communication between intracellular organelles under stress conditions.

Keywords:  IRE1α; endoplasmic reticulum; stress sensor; unfolded protein response

DOI:  https://doi.org/10.1080/19768354.2021.2020901
Int J Mol Sci. 2022 Jan 11. pii: 780. [Epub ahead of print]23(2):

Impact of ER Stress and ER-Mitochondrial Crosstalk in Huntington's Disease.

Shuvadeep Maity, Pragya Komal, Vaishali Kumar, Anshika Saxena, Ayesha Tungekar, Vaani Chandrasekar.

  Accumulation of misfolded proteins is a common phenomenon of several neurodegenerative diseases. The misfolding of proteins due to abnormal polyglutamine (PolyQ) expansions are linked to the development of PolyQ diseases including Huntington's disease (HD). Though the genetic basis of PolyQ repeats in HD remains prominent, the primary molecular basis mediated by PolyQ toxicity remains elusive. Accumulation of misfolded proteins in the ER or disruption of ER homeostasis causes ER stress and activates an evolutionarily conserved pathway called Unfolded protein response (UPR). Protein homeostasis disruption at organelle level involving UPR or ER stress response pathways are found to be linked to HD. Due to dynamic intricate connections between ER and mitochondria, proteins at ER-mitochondria contact sites (mitochondria associated ER membranes or MAMs) play a significant role in HD development. The current review aims at highlighting the most updated information about different UPR pathways and their involvement in HD disease progression. Moreover, the role of MAMs in HD progression has also been discussed. In the end, the review has focused on the therapeutic interventions responsible for ameliorating diseased states via modulating either ER stress response proteins or modulating the expression of ER-mitochondrial contact proteins.

Keywords:  ER; ER stress; Huntington’s disease (HD); mitochondria; mitochondria associated ER membranes (MAM)

DOI:  https://doi.org/10.3390/ijms23020780
J Biol Chem. 2022 Jan 13. pii: S0021-9258(22)00029-1. [Epub ahead of print] 101589

Immunosuppressive calcineurin inhibitor cyclosporine A induces pro-apoptotic endoplasmic reticulum stress in renal tubular cells.

Duygu Elif Yilmaz, Karin Kirschner, Hasan Demirci, Nina Himmerkus, Sebastian Bachmann, Kerim Mutig.

  Current immunosuppressive strategies following organ transplantation rely on the calcineurin inhibitors (CNI) cyclosporine A (CsA) or tacrolimus (Tac). Both drugs are nephrotoxic, but CsA has been associated with greater renal damage compared to Tac. Calcineurin dephosphorylates NFAT transcription factors to promote T cell activation. CsA inhibits calcineurin by forming complexes with cyclophilins, whose chaperone function is essential for proteostasis. We hypothesized that stronger toxicity of CsA may be related with suppression of cyclophilins, leading to endoplasmic reticulum (ER)-stress and unfolded protein response (UPR) in the kidney epithelia. Effects of CsA and Tac (10 μM for 6 h each) were evaluated in cultured HEK 293 cells, primary human renal proximal tubule (PT) cells, freshly isolated rat PTs, and in knockout HEK 293 cell lines lacking the critical ER-stress sensors PERK or ATF6. Compared to Tac treatment, CsA induced a significantly stronger UPR in native cultured cells and isolated PTs. Evaluation of pro-apoptotic (cleaved caspase-3 and Bax) and anti-apoptotic markers (BCL-2) suggested an enhanced apoptotic rate in CsA- compared to Tac-treated cells as well. Similar to CsA treatment, knockdown of cyclophilin A or B by siRNA augmented the UPR marker CHOP and cCas-3 levels, while deletion of PERK or ATF6 blunted CsA-induced UPR. Application of the chemical chaperones TUDCA or 4-PBA alleviated CsA-induced ER-stress. In summary, inhibition of cyclophilin chaperone function with ensuing ER-stress and pro-apoptotic UPR aggravates CsA toxicity. We conclude that pharmacological modulation of UPR has potential to alleviate renal side effects of CsA treatment.

Keywords:  calcineurin; cyclosporine A; endoplasmic reticulum stress; tacrolimus; transplantation; unfolded protein response

DOI:  https://doi.org/10.1016/j.jbc.2022.101589
Free Radic Biol Med. 2022 Jan 13. pii: S0891-5849(22)00017-X. [Epub ahead of print]

ER reductive stress caused by Ero1α S-nitrosation accelerates senescence.

Xinhua Qiao, Yingmin Zhang, Aojun Ye, Yini Zhang, Ting Xie, Zhenyu Lv, Cang Shi, Dongli Wu, Boyu Chu, Xun Wu, Weiqi Zhang, Ping Wang, Guang-Hui Liu, Chih-Chen Wang, Lei Wang, Chang Chen.

  Oxidative stress in aging has attracted much attention; however, the role of reductive stress in aging remains largely unknown. Here, we report that the endoplasmic reticulum (ER) undergoes reductive stress during replicative senescence, as shown by specific glutathione and H2O2 fluorescent probes. We constructed an ER-specific reductive stress cell model by ER-specific catalase overexpression and observed accelerated senescent phenotypes accompanied by disrupted proteostasis and a compromised ER unfolded protein response (UPR). Mechanistically, S-nitrosation of the pivotal ER sulfhydryl oxidase Ero1α led to decreased activity, therefore resulting in reductive stress in the ER. Inhibition of inducible nitric oxide synthase decreased the level of Ero1α S-nitrosation and decreased cellular senescence. Moreover, the expression of constitutively active Ero1α restored an oxidizing state in the ER and successfully rescued the senescent phenotypes. Our results uncover a new mechanism of senescence promoted by ER reductive stress and provide proof-of-concept that maintaining the oxidizing power of the ER and organelle-specific precision redox regulation could be valuable future geroprotective strategies.

Keywords:  Aging; Endoplasmic reticulum (ER); Ero1α; Proteostasis; Reductive stress; S-Nitrosation/S-nitrosylation; Senescence; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.006
Diabetes. 2022 Jan 14. pii: db210443. [Epub ahead of print]

PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes.

Bernat Elvira, Valerie Vandenbempt, Julia Bauzá-Martinez, Raphaël Crutzen, Javier Negueruela, Hazem Ibrahim, Matthew L Winder, Manoja K Brahma, Beata Vekeriotaite, Pieter-Jan Martens, Sumeet Pal Singh, Fernando Rossello, Pascale Lybaert, Timo Otonkoski, Conny Gysemans, Wei Wu, Esteban N Gurzov.

Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell dysfunction. Here, we assessed the global protein and individual PTP profiles in the pancreas from early onset non-obese diabetic (NOD) mice treated with an anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist. The treatment reversed hyperglycemia and we observed enhanced expression of PTPN2, a PTP family member and T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the pancreatic islets. To address the functional role of PTPN2 in β-cells, we generated PTPN2-deficient human stem cell-derived β-like and EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates type I and type II interferon signaling networks and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to positively modulate the Ca2+-dependent unfolded protein response and ER stress outcome in β-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.

DOI: https://doi.org/10.2337/db21-0443
Cancer Res. 2022 Jan 19. pii: canres.2229.2021. [Epub ahead of print]

Targeting squalene epoxidase interrupts homologous recombination via the ER stress response and promotes radiotherapy efficacy.

Zhipeng Hong, Tao Liu, Lingfeng Wan, Pengyan Fa, Pankaj Kumar, Yanan Cao, Chandra Bhushan Prasad, Zhaojun Qiu, Joseph Liu, Hongbing Wang, Zaibo Li, Qi-En Wang, Peixuan Guo, Deliang Guo, Ayse S Yilmaz, Lanchun Lu, Ioanna Papandreou, Naduparambil K Jacob, Chunhong Yan, Xiaoli Zhang, Qing-Bai She, Zhefu Ma, Junran Zhang.

Over 50% of all cancer patients are treated with radiation therapy (RT). However, RT is often insufficient as a monotherapy and requires a non-toxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer (BC) and non-small cell lung cancer (NSCLC), two cancers often treated with RT. SQLE-positive immunohistochemical staining was observed in 68% of BC and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of poor prognosis, and pharmacological inhibition of SQLE enhanced breast and lung cancer cell radiosensitivity. In addition, SQLE inhibition enhanced sensitivity to PARP inhibition. Inhibition of SQLE interrupted homologous recombination by suppressing ATM activity via the translational upregulation of wild-type p53-induced phosphatase (WIP1), regardless of the p53 status. SQLE inhibition and subsequent squalene accumulation promoted this upregulation by triggering the endoplasmic reticulum (ER) stress response. Collectively, these results identify a novel tumor-specific radiosensitizer by revealing unrecognized crosstalk between squalene metabolites, ER stress, and the DNA damage response (DDR). Although SQLE inhibitors have been used as antifungal agents in the clinic, they have not yet been used as antitumor agents. Repurposing existing SQLE-inhibiting drugs may provide new cancer treatments.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-2229