bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023‒09‒17
twelve papers selected by
Susan Logue, University of Manitoba
  1. CD44 correlates with longevity and enhances basal ATF6 activity and ER stress resistance.
  2. The Role of Endoplasmic Reticulum in Lipotoxicity during MASLD Pathogenesis.
  3. Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT.
  4. ER translocon inhibitor ipomoeassin F inhibits triple-negative breast cancer growth via blocking ER molecular chaperones.
  5. Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.
  6. Endoplasmic Reticulum Stress in Systemic Lupus Erythematosus and Lupus Nephritis: Potential Therapeutic Target.
  7. Protein disulfide isomerase family mediated redox regulation in cancer.
  8. Recent advances in small molecule and peptide inhibitors of glucose-regulated protein 78 for cancer therapy.
  9. Competition for calnexin binding regulates secretion and turnover of misfolded GPI-anchored proteins.
  10. Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid.
  11. High-resolution imaging of presynaptic ER networks in Atlastin mutants.
  12. Proteostasis Network Modulation Promotes Resistance to KRAS Inhibitors.
  1. Cell Rep. 2023 Sep 13. pii: S2211-1247(23)01142-7. [Epub ahead of print]42(9): 113130
    CD44 correlates with longevity and enhances basal ATF6 activity and ER stress resistance.
    Masaki Takasugi, Naoko Ohtani, Kazuaki Takemura, Stephan Emmrich, Frances T Zakusilo, Yuya Yoshida, Nobuyuki Kutsukake, John N Mariani, Martha S Windrem, Devin Chandler-Militello, Steven A Goldman, Junko Satoh, Shinji Ito, Andrei Seluanov, Vera Gorbunova.
      The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR's resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals. Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues. We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity.
    Keywords:  ATF6; CD44; CP: Cell biology; comparative transcriptomics; longevity; naked mole rat; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113130
  2. Am J Pathol. 2023 Sep 07. pii: S0002-9440(23)00314-0. [Epub ahead of print]
    The Role of Endoplasmic Reticulum in Lipotoxicity during MASLD Pathogenesis.
    Nanditha Venkatesan, Luke C Doskey, Harmeet Malhi.
      Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic-dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: Inositol Requiring Enzyme1α, PKR-like ER Kinase and Activating Transcription Factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins. The ER is also intimately connected with lipid metabolism, including de novo ceramide synthesis, phospholipid and cholesterol synthesis, and lipid droplet formation. Following their activation, the UPR transducers also regulate lipogenic pathways in the liver. With persistent ER stress, cellular adaptation fails resulting in hepatocyte apoptosis, a pathological marker of liver disease. In addition to the ER-nucleus signaling activated by the UPR, the ER can interact with other organelles via membrane contact sites. Modulating intracellular communication between ER and endosomes, lipid droplets and mitochondria to restore ER homeostasis could have therapeutic efficacy in ameliorating liver disease. Recent studies have also demonstrated that cells can convey ER stress by the release of extracellular vesicles. In this review, lipotoxic ER stress and the central role of the ER in communicating ER stress to other intracellular organelles in MASLD pathogenesis is discussed.
    Keywords:  endoplasmic reticulum stress; lipotoxicity; metabolic liver disease; nonalcoholic steatohepatitis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.ajpath.2023.08.007
  3. Cell Death Differ. 2023 Sep 13.
    Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT.
    Yujin Kwon, Jiyoon Kim, Su-Yeon Cho, Yoon Jin Kang, Jongsoo Lee, Jaeyoung Kwon, Hyungjin Rhee, Sebastian Bauer, Hyung-Sik Kim, Esak Lee, Han Sang Kim, Jae Hung Jung, Hoguen Kim, Won Kyu Kim.
      Gastrointestinal stromal tumors (GISTs) frequently show KIT mutations, accompanied by overexpression and aberrant localization of mutant KIT (MT-KIT). As previously established by multiple studies, including ours, we confirmed that MT-KIT initiates downstream signaling in the Golgi complex. Basic leucine zipper nuclear factor 1 (BLZF1) was identified as a novel MT-KIT-binding partner that tethers MT-KIT to the Golgi complex. Sustained activation of activated transcription factor 6 (ATF6), which belongs to the unfolded protein response (UPR) family, alleviates endoplasmic reticulum (ER) stress by upregulating chaperone expression, including heat shock protein 90 (HSP90), which assists in MT-KIT folding. BLZF1 knockdown and ATF6 inhibition suppressed both imatinib-sensitive and -resistant GIST in vitro. ATF6 inhibitors further showed potent antitumor effects in GIST xenografts, and the effect was enhanced with ER stress-inducing drugs. ATF6 activation was frequently observed in 67% of patients with GIST (n = 42), and was significantly associated with poorer relapse-free survival (P = 0.033). Overall, GIST bypasses ER quality control (QC) and ER stress-mediated cell death via UPR activation and uses the QC-free Golgi to initiate signaling.
    DOI:  https://doi.org/10.1038/s41418-023-01220-2
  4. Int J Biol Sci. 2023 ;19(13): 4020-4035
    ER translocon inhibitor ipomoeassin F inhibits triple-negative breast cancer growth via blocking ER molecular chaperones.
    Shishi Tao, Eun Ju Yang, Guanghui Zong, Pui Kei Mou, Guowen Ren, Yue Pu, Liang Chen, Ho Jeong Kwon, Jianhong Zhou, Zhijian Hu, Arman Khosravi, Qingyang Zhang, Yuchun Du, Wei Q Shi, Joong Sup Shim.
      Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer where no effective therapy has been developed. Here, we report that the natural product ER translocon inhibitor ipomoeassin F is a selective inhibitor of TNBC cell growth. A proteomic analysis of TNBC cells revealed that ipomoeassin F significantly reduced the levels of ER molecular chaperones, including PDIA6 and PDIA4, and induced ER stress, unfolded protein response (UPR) and autophagy in TNBC cells. Mechanistically, ipomoeassin F, as an inhibitor of Sec61α-containing ER translocon, blocks ER translocation of PDIA6, inducing its proteasomal degradation. Silencing of PDIA6 or PDIA4 by RNA interferences or treatment with a small molecule inhibitor of the protein disulfide isomerases in TNBC cells successfully recapitulated the ipomoeassin F phenotypes, including the induction of ER stress, UPR and autophagy, suggesting that the reduction of PDIAs is the key mediator of the pharmacological effects of ipomoeassin F. Moreover, ipomoeassin F significantly suppressed TNBC growth in a mouse tumor xenograft model, with a marked reduction in PDIA6 and PDIA4 levels in the tumor samples. Our study demonstrates that Sec61α-containing ER translocon and PDIAs are potential drug targets for TNBC and suggests that ipomoeassin F could serve as a lead for developing ER translocon-targeted therapy for TNBC.
    Keywords:  ER stress; ER translocon; Ipomoeassin F; PDIA4; PDIA6; TNBC
    DOI:  https://doi.org/10.7150/ijbs.82012
  5. Sci Adv. 2023 Sep 15. 9(37): eadh0831
    Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.
    Ebru Boslem, Saskia Reibe, Rodrigo Carlessi, Benoit Smeuninx, Surafel Tegegne, Casey L Egan, Emma McLennan, Lauren V Terry, Max Nobis, Andre Mu, Cameron Nowell, Neil Horadagoda, Natalie A Mellett, Paul Timpson, Matthew Jones, Elena Denisenko, Alistair R R Forrest, Janina E E Tirnitz-Parker, Peter J Meikle, Stefan Rose-John, Michael Karin, Mark A Febbraio.
      The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the MUP-uPA mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated MUP-uPA mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.
    DOI:  https://doi.org/10.1126/sciadv.adh0831
  6. J Immunol Res. 2023 ;2023 7625817
    Endoplasmic Reticulum Stress in Systemic Lupus Erythematosus and Lupus Nephritis: Potential Therapeutic Target.
    Hui-Yuan Li, Li-Feng Huang, Xiao-Rong Huang, Dan Wu, Xiao-Cui Chen, Ji-Xin Tang, Ning An, Hua-Feng Liu, Chen Yang.
      Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Approximately one-third to two-thirds of the patients with SLE progress to lupus nephritis (LN). The pathogenesis of SLE and LN has not yet been fully elucidated, and effective treatment for both conditions is lacking. The endoplasmic reticulum (ER) is the largest intracellular organelle and is a site of protein synthesis, lipid metabolism, and calcium storage. Under stress, the function of ER is disrupted, and the accumulation of unfolded or misfolded proteins occurs in ER, resulting in an ER stress (ERS) response. ERS is involved in the dysfunction of B cells, macrophages, T cells, dendritic cells, neutrophils, and other immune cells, causing immune system disorders, such as SLE. In addition, ERS is also involved in renal resident cell injury and contributes to the progression of LN. The molecular chaperones, autophagy, and proteasome degradation pathways inhibit ERS and restore ER homeostasis to improve the dysfunction of immune cells and renal resident cell injury. This may be a therapeutic strategy for SLE and LN. In this review, we summarize advances in this field.
    DOI:  https://doi.org/10.1155/2023/7625817
  7. Adv Cancer Res. 2023 ;pii: S0065-230X(23)00052-0. [Epub ahead of print]160 83-106
    Protein disulfide isomerase family mediated redox regulation in cancer.
    Zhi-Wei Ye, Jie Zhang, Muhammad Aslam, Anna Blumental-Perry, Kenneth D Tew, Danyelle M Townsend.
      Protein disulfide isomerase (PDI) and its superfamilies are mainly endoplasmic reticulum (ER) resident proteins with essential roles in maintaining cellular homeostasis, via thiol oxidation/reduction cycles, chaperoning, and isomerization of client proteins. Since PDIs play an important role in ER homeostasis, their upregulation supports cell survival and they are found in a variety of cancer types. Despite the fact that the importance of PDI to tumorigenesis remains to be understood, it is emerging as a new therapeutic target in cancer. During the past decade, several PDI inhibitors has been developed and commercialized, but none has been approved for clinical use. In this review, we discuss the properties and redox regulation of PDIs within the ER and provide an overview of the last 5 years of advances regarding PDI inhibitors.
    Keywords:  Cancer; ER stress; Inhibitors; Protein disulfide isomerase; Redox regualtion
    DOI:  https://doi.org/10.1016/bs.acr.2023.06.001
  8. Eur J Med Chem. 2023 Sep 04. pii: S0223-5234(23)00759-6. [Epub ahead of print]261 115792
    Recent advances in small molecule and peptide inhibitors of glucose-regulated protein 78 for cancer therapy.
    Weikai Guo, Manjie Wang, Zhengfan Yang, Danyang Liu, Borui Ma, Yanqun Zhao, Yihua Chen, Yanzhong Hu.
      Glucose-regulated protein 78 (GRP78) is one of key endoplasmic reticulum (ER) chaperone proteins that regulates the unfolded protein response (UPR) to maintain ER homeostasis. As a core factor in the regulation of the UPR, GRP78 takes a critical part in the cellular processes required for tumorigenesis, such as proliferation, metastasis, anti-apoptosis, immune escape and chemoresistance. Overexpression of GRP78 is closely correlated with tumorigenesis and poor prognosis in various malignant tumors. Targeting GRP78 is regarded as a potentially promising therapeutic strategy for cancer therapy. Although none of the GRP78 inhibitors have been approved to date, there have been several studies of GRP78 inhibitors. Herein, we comprehensively review the structure, physiological functions of GRP78 and the recent progress of GRP78 inhibitors, and discuss the structures, in vitro and in vivo efficacies, and merits and demerits of these inhibitors to inspire further research. Additionally, the feasibility of GRP78-targeting proteolysis-targeting chimeras (PROTACs), disrupting GRP78 cochaperone interactions, or covalent inhibition are also discussed as novel strategies for drugs discovery targeting GRP78, with the hope that these strategies can provide new opportunities for targeted GRP78 antitumor therapy.
    DOI:  https://doi.org/10.1016/j.ejmech.2023.115792
  9. J Cell Biol. 2023 Oct 02. pii: e202108160. [Epub ahead of print]222(10):
    Competition for calnexin binding regulates secretion and turnover of misfolded GPI-anchored proteins.
    Amber M Cheatham, Nishi Raj Sharma, Prasanna Satpute-Krishnan.
      In mammalian cells, misfolded glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are cleared out of the ER to the Golgi via a constitutive and a stress-inducible pathway called RESET. From the Golgi, misfolded GPI-APs transiently access the cell surface prior to rapid internalization for lysosomal degradation. What regulates the release of misfolded GPI-APs for RESET during steady-state conditions and how this release is accelerated during ER stress is unknown. Using mutants of prion protein or CD59 as model misfolded GPI-APs, we demonstrate that inducing calnexin degradation or upregulating calnexin-binding glycoprotein expression triggers the release of misfolded GPI-APs for RESET. Conversely, blocking protein synthesis dramatically inhibits the dissociation of misfolded GPI-APs from calnexin and subsequent turnover. We demonstrate an inverse correlation between newly synthesized calnexin substrates and RESET substrates that coimmunoprecipitate with calnexin. These findings implicate competition by newly synthesized substrates for association with calnexin as a key factor in regulating the release of misfolded GPI-APs from calnexin for turnover via the RESET pathway.
    DOI:  https://doi.org/10.1083/jcb.202108160
  10. Front Immunol. 2023 ;14 1204126
    Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid.
    Margaud Iovino, Megan Colonval, Chloé Wilkin, Laurent L'homme, Cédric Lassence, Manon Campas, Olivier Peulen, Pascal de Tullio, Jacques Piette, Sylvie Legrand-Poels.
      In obesity, adipose tissue infiltrating macrophages acquire a unique pro-inflammatory polarization, thereby playing a key role in the development of chronic inflammation and Type 2 diabetes. Increased saturated fatty acids (SFAs) levels have been proposed to drive this specific polarization. Accordingly, we investigated the immunometabolic reprogramming in SFA-treated human macrophages. As expected, RNA sequencing highlighted a pro-inflammatory profile but also metabolic signatures including glycolysis and hypoxia as well as a strong unfolded protein response. Glycolysis upregulation was confirmed in SFA-treated macrophages by measuring glycolytic gene expression, glucose uptake, lactate production and extracellular acidification rate. Like in LPS-stimulated macrophages, glycolysis activation in SFA-treated macrophages was dependent on HIF-1α activation and fueled the production of pro-inflammatory cytokines. SFAs and LPS both induced IRE1α endoribonuclease activity, as demonstrated by XBP1 mRNA splicing, but with different kinetics matching HIF-1α activation and the glycolytic gene expression. Interestingly, the knockdown of IRE1α and/or the pharmacological inhibition of its RNase activity prevented HIF-1α activation and significantly decreased glycolysis upregulation. Surprisingly, XBP1s appeared to be dispensable, as demonstrated by the lack of inhibiting effect of XBP1s knockdown on glycolytic genes expression, glucose uptake, lactate production and HIF-1α activation. These experiments demonstrate for the first time a key role of IRE1α in HIF-1α-mediated glycolysis upregulation in macrophages stimulated with pro-inflammatory triggers like LPS or SFAs through XBP1s-independent mechanism. IRE1 could mediate this novel function by targeting other transcripts (mRNA or pre-miRNA) through a mechanism called regulated IRE1-dependent decay or RIDD. Deciphering the underlying mechanisms of this novel IRE1 function might lead to novel therapeutic targets to curtail sterile obesity- or infection-linked inflammation.
    Keywords:  HIF-1α; IRE1α; glycolysis; inflammation; macrophages; saturated fatty acid
    DOI:  https://doi.org/10.3389/fimmu.2023.1204126
  11. bioRxiv. 2023 Sep 02. pii: 2023.09.01.555994. [Epub ahead of print]
    High-resolution imaging of presynaptic ER networks in Atlastin mutants.
    Mónica C Quiñones-Frías, Dina M Ocken, Avital Rodal.
      The endoplasmic reticulum (ER) is a continuous organelle that extends to the periphery of neurons and regulates many neuronal functions including neurite outgrowth, neurotransmission, and synaptic plasticity. Mutations in proteins that control ER shape are linked to the neurodegenerative disorder Hereditary Spastic Paraplegia (HSP). However, the ultrastructure and dynamics of the neuronal ER have been under-investigated, particularly at presynaptic terminals. Here we developed new super-resolution and live imaging methods in D. melanogaster larval motor neurons to investigate ER structure at presynaptic terminals from wild-type animals, and in null mutants of the HSP gene Atlastin. Previous studies indicated diffuse localization of an ER lumen marker at Atlastin mutant presynaptic terminals, which was attributed to ER fragmentation. By contrast, we found using an ER membrane marker that the ER in Atlastin mutants formed robust networks. Further, our high-resolution imaging results suggest that overexpression of luminal ER proteins in Atlastin mutants causes their progressive displacement to the cytosol at synapses, perhaps due to proteostatic stress and/or changes in ER membrane integrity. Remarkably, these luminal ER proteins remain correctly localized in cell bodies, axons, and other cell types such as body wall muscles, suggesting that ER tubules at synapses have unique structural and functional characteristics. This displacement phenotype has not been reported in numerous studies of Atlastin in non-neuronal cells, emphasizing the importance of conducting experiments in neurons when investigating the mechanisms leading to upper motor neuron dysfunction in HSP.
    DOI:  https://doi.org/10.1101/2023.09.01.555994
  12. Cancer Discov. 2023 Sep 15. OF1
    Proteostasis Network Modulation Promotes Resistance to KRAS Inhibitors.
      IRE1α-mediated proteostasis reprogramming is a key resistance mechanism to KRAS inhibitors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-148
This page is being maintained by Thomas Krichel. It was last updated on 2023‒09‒17 at 14:59.