bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020–04–19
seven papers selected by
Susan Logue, University of Manitoba
  1. The Impact of the ER Unfolded Protein Response on Cancer Initiation and Progression: Therapeutic Implications.
  2. The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling.
  3. The emerging role of XBP1 in cancer.
  4. ER stress activates immunosuppressive network: implications for aging and Alzheimer's disease.
  5. HSF1 is required for induction of mitochondrial chaperones during the mitochondrial unfolded protein response.
  6. Calnexin cycle - structural features of the ER chaperone system.
  7. The Role of HSF1 and the Chaperone Network in the Tumor Microenvironment.
  1. Adv Exp Med Biol. 2020 ;1243 113-131
    The Impact of the ER Unfolded Protein Response on Cancer Initiation and Progression: Therapeutic Implications.
    Cynthia Lebeaupin, Jing Yong, Randal J Kaufman.
      Cellular stress induced by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates an elaborate signalling network termed the unfolded protein response (UPR). This adaptive response is mediated by the transmembrane signal transducers IRE1, PERK, and ATF6 to decide cell fate of recovery or death. In malignant cells, UPR signalling may be required to maintain ER homeostasis and survival in the tumor microenvironment characterized by oxidative stress, hypoxia, lactic acidosis and compromised protein folding. Here we provide an overview of the ER response to cellular stress and how the sustained activation of this network enables malignant cells to develop tumorigenic, metastatic and drug-resistant capacities to thrive under adverse conditions. Understanding the complexity of ER stress responses and how to target the UPR in disease will have significant potential for novel future therapeutics.
    Keywords:  ATF4; ATF6; BiP; Cancer; Chaperones; ER stress; IRE1α; Oxidative stress; PERK; UPR; XBP1
    DOI:  https://doi.org/10.1007/978-3-030-40204-4_8
  2. Immunity. 2020 Apr 14. pii: S1074-7613(20)30117-5. [Epub ahead of print]52(4): 668-682.e7
    The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling.
    Eslam Mohamed, Rosa A Sierra, Jimena Trillo-Tinoco, Yu Cao, Patrick Innamarato, Kyle K Payne, Alvaro de Mingo Pulido, Jessica Mandula, Shuzhong Zhang, Paul Thevenot, Subir Biswas, Sarah K Abdalla, Tara Lee Costich, Kay Hänggi, Carmen M Anadon, Elsa R Flores, Eric B Haura, Shikhar Mehrotra, Shari Pilon-Thomas, Brian Ruffell, David H Munn, Juan R Cubillos-Ruiz, Jose R Conejo-Garcia, Paulo C Rodriguez.
      The primary mechanisms supporting immunoregulatory polarization of myeloid cells upon infiltration into tumors remain largely unexplored. Elucidation of these signals could enable better strategies to restore protective anti-tumor immunity. Here, we investigated the role of the intrinsic activation of the PKR-like endoplasmic reticulum (ER) kinase (PERK) in the immunoinhibitory actions of tumor-associated myeloid-derived suppressor cells (tumor-MDSCs). PERK signaling increased in tumor-MDSCs, and its deletion transformed MDSCs into myeloid cells that activated CD8+ T cell-mediated immunity against cancer. Tumor-MDSCs lacking PERK exhibited disrupted NRF2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. Moreover, reduced NRF2 signaling in PERK-deficient MDSCs elicited cytosolic mitochondrial DNA elevation and, consequently, STING-dependent expression of anti-tumor type I interferon. Reactivation of NRF2 signaling, conditional deletion of STING, or blockade of type I interferon receptor I restored the immunoinhibitory potential of PERK-ablated MDSCs. Our findings demonstrate the pivotal role of PERK in tumor-MDSC functionality and unveil strategies to reprogram immunosuppressive myelopoiesis in tumors to boost cancer immunotherapy.
    Keywords:  ER stress; MDSCs; NRF2; PERK; STING; tumor immunity; type I IFN; unfolded protein responses
    DOI:  https://doi.org/10.1016/j.immuni.2020.03.004
  3. Biomed Pharmacother. 2020 Apr 12. pii: S0753-3322(20)30260-2. [Epub ahead of print]127 110069
    The emerging role of XBP1 in cancer.
    Shanshan Chen, Jing Chen, Xin Hua, Yue Sun, Rui Cui, Jun Sha, Xiaoli Zhu.
      X-box binding protein 1 (XBP1) is a unique basic-region leucine zipper (bZIP) transcription factor whose dynamic form is controlled by an alternative splicing response upon disturbance of homeostasis in the endoplasmic reticulum (ER) and activation of the unfolded protein response (UPR). XBP1 was first distinguished as a key regulator of major histocompatibility complex (MHC) class II gene expression in B cells. XBP1 communicates with the foremost conserved signalling component of the UPR and is essential for cell fate determination in response to ER stress (ERS). Here, we review recent advances in our understanding of this multifaceted translation component in cancer. In this review, we briefly discuss the role of XBP1 mediators in the UPR and the transcriptional function of XBP1. In addition, we describe how XBP1 operates as a key factor in tumour progression and metastasis. We mainly review XBP1's expression, function and prognostic value in research on solid tumours. Finally, we discuss multiple approaches, especially those involving XBP1, that overcome the immunosuppressive effect of the UPR in cancer that could potentially be useful as antitumour therapies.
    Keywords:  Cancer; Endoplasmic reticulum stress; Inositol-requiring enzyme 1; Unfolded protein response; X-box binding protein 1
    DOI:  https://doi.org/10.1016/j.biopha.2020.110069
  4. J Mol Med (Berl). 2020 Apr 11.
    ER stress activates immunosuppressive network: implications for aging and Alzheimer's disease.
    Antero Salminen, Kai Kaarniranta, Anu Kauppinen.
      The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and ATF6 transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer's disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer's disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer's disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.
    Keywords:  Ageing; Immunometabolism; Immunosenescence; Immunosuppression; Inflammaging; Neurodegeneration
    DOI:  https://doi.org/10.1007/s00109-020-01904-z
  5. FEBS Open Bio. 2020 Apr 17.
    HSF1 is required for induction of mitochondrial chaperones during the mitochondrial unfolded protein response.
    Arpit Katiyar, Mitsuaki Fujimoto, Ke Tan, Ai Kurashima, Pratibha Srivastava, Mariko Okada, Ryosuke Takii, Akira Nakai.
      The mitochondrial unfolded protein response (UPRmt ) is characterized by the transcriptional induction of mitochondrial chaperone and protease genes in response to impaired mitochondrial proteostasis, and is regulated by ATF5 and CHOP in mammalian cells. However, the detailed mechanisms underlying the UPRmt are currently unclear. Here, we show that HSF1 is required for activation of mitochondrial chaperone genes, including HSP60, HSP10, and mtHSP70, in mouse embryonic fibroblasts during inhibition of matrix chaperone TRAP1, protease Lon, or electron transfer complex 1 activity. HSF1 bound constitutively to mitochondrial chaperone gene promoters, and we observed that its occupancy was remarkably enhanced at different levels during the UPRmt . Furthermore, HSF1 supported maintenance of mitochondrial function under the same conditions. These results demonstrate that HSF1 is required for induction of mitochondrial chaperones during the UPRmt , and thus it may be one of the guardians of mitochondrial function under conditions of impaired mitochondrial proteostasis.
    Keywords:  HSF1; SSBP1; heat shock protein; mitochondria; proteostasis; proteotoxic stress
    DOI:  https://doi.org/10.1002/2211-5463.12863
  6. FEBS J. 2020 Apr 13.
    Calnexin cycle - structural features of the ER chaperone system.
    Guennadi Kozlov, Kalle Gehring.
      The endoplasmic reticulum (ER) is the major folding compartment for secreted and membrane proteins and is the site of a specific chaperone system, the calnexin cycle, for folding N-glycosylated proteins. Recent structures of components of the calnexin cycle have deepened our understanding of quality control mechanisms and protein folding pathways in the ER. In the calnexin cycle, proteins carrying monoglucosylated glycans bind to the lectin chaperones calnexin and calreticulin, which recruit a variety of function-specific chaperones to mediate protein disulfide formation, proline isomerization, and general protein folding. Upon trimming by glucosidase II, the glycan without an inner glucose residue is no longer able to bind to the lectin chaperones. For proteins that have not yet folded properly, the enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) acts as a checkpoint by adding a glucose back to the N-glycan. This allows the misfolded proteins to re-associate with calnexin and calreticulin for additional rounds of chaperone-mediated refolding and prevents them from exiting the ERs. Here, we review progress in structural studies of the calnexin cycle, which reveal common features of how lectin chaperones recruit function-specific chaperones and how UGGT recognizes misfolded proteins.
    Keywords:  CypB; ERp29; ERp57; PDI; UGGT; calnexin; calnexin cycle; calreticulin; endoplasmic reticulum; protein folding
    DOI:  https://doi.org/10.1111/febs.15330
  7. Adv Exp Med Biol. 2020 ;1243 101-111
    The Role of HSF1 and the Chaperone Network in the Tumor Microenvironment.
    Nil Grunberg, Oshrat Levi-Galibov, Ruth Scherz-Shouval.
      Tumors are stressful environments. As tumors evolve from single mutated cancer cells into invasive malignancies they must overcome various constraints and barriers imposed by a hostile microenvironment. To achieve this, cancer cells recruit and rewire cells in their microenvironment to become pro-tumorigenic. We propose that chaperones are vital players in this process, and that activation of stress responses helps tumors adapt and evolve into aggressive malignancies, by enabling phenotypic plasticity in the tumor microenvironment (TME). In this chapter we will review evidence supporting non-cancer-cell-autonomous activity of chaperones in human patients and mouse models of cancer, discuss the mechanisms by which this non-cell-autonomous activity is mediated and provide an evolutionary perspective on the basis of this phenomenon.
    Keywords:  Cancer; Cancer-associated fibroblasts; Chaperones; ER-stress; HSF1; Heat shock; Stress responses; Tumor microenvironment; UPR
    DOI:  https://doi.org/10.1007/978-3-030-40204-4_7
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