bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022‒04‒24
eight papers selected by
Susan Logue
University of Manitoba
  1. Antigen-derived peptides engage the ER stress sensor IRE1α to curb dendritic cell cross-presentation.
  2. Reshaping endoplasmic reticulum quality control through the unfolded protein response.
  3. A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
  4. Cancer cells adapt FAM134B/BiP mediated ER-phagy to survive hypoxic stress.
  5. Glycotherapy: A New Paradigm in Breast Cancer Research.
  6. Restoration of ER proteostasis attenuates remote apoptotic cell death after spinal cord injury by reducing autophagosome overload.
  7. The mammalian rhomboid protein RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets.
  8. Mitochondria-Endoplasmic Reticulum Contacts: The Promising Regulators in Diabetic Cardiomyopathy.
  1. J Cell Biol. 2022 Jun 06. pii: e202111068. [Epub ahead of print]221(6):
    Antigen-derived peptides engage the ER stress sensor IRE1α to curb dendritic cell cross-presentation.
    Ofer Guttman, Adrien Le Thomas, Scot Marsters, David A Lawrence, Lauren Gutgesell, Iratxe Zuazo-Gaztelu, Jonathan M Harnoss, Simone M Haag, Aditya Murthy, Geraldine Strasser, Zora Modrusan, Thomas Wu, Ira Mellman, Avi Ashkenazi.
      Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER), bind to major histocompatibility type I (MHC-I) protein complexes, and are transported to the cell surface for cross-presentation. DCs can exhibit activation of the ER stress sensor IRE1α without ER stress, but the underlying mechanism remains obscure. Here, we show that antigen-derived hydrophobic peptides can directly engage ER-resident IRE1α, masquerading as unfolded proteins. IRE1α activation depletes MHC-I heavy-chain mRNAs through regulated IRE1α-dependent decay (RIDD), curtailing antigen cross-presentation. In tumor-bearing mice, IRE1α disruption increased MHC-I expression on tumor-infiltrating DCs and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1α inhibition synergized with anti-PD-L1 antibody treatment to cause tumor regression. Our findings identify an unexpected cell-biological mechanism of antigen-driven IRE1α activation in DCs, revealing translational potential for cancer immunotherapy.
    DOI:  https://doi.org/10.1083/jcb.202111068
  2. Mol Cell. 2022 Apr 21. pii: S1097-2765(22)00263-5. [Epub ahead of print]82(8): 1477-1491
    Reshaping endoplasmic reticulum quality control through the unfolded protein response.
    R Luke Wiseman, Jaleh S Mesgarzadeh, Linda M Hendershot.
      Endoplasmic reticulum quality control (ERQC) pathways comprising chaperones, folding enzymes, and degradation factors ensure the fidelity of ER protein folding and trafficking to downstream secretory environments. However, multiple factors, including tissue-specific secretory proteomes, environmental and genetic insults, and organismal aging, challenge ERQC. Thus, a key question is: how do cells adapt ERQC to match the diverse, ever-changing demands encountered during normal physiology and in disease? The answer lies in the unfolded protein response (UPR), a signaling mechanism activated by ER stress. In mammals, the UPR comprises three signaling pathways regulated downstream of the ER membrane proteins IRE1, ATF6, and PERK. Upon activation, these UPR pathways remodel ERQC to alleviate cellular stress and restore ER function. Here, we describe how UPR signaling pathways adapt ERQC, highlighting their importance for maintaining ER function across tissues and the potential for targeting the UPR to mitigate pathologies associated with protein misfolding diseases.
    Keywords:  ATF6; ER-associated degradation; ERAD; IRE1; PERK; XBP1s; amyloid; chaperone; loss-of-function disease; protein aggregation; protein misfolding disease
    DOI:  https://doi.org/10.1016/j.molcel.2022.03.025
  3. Elife. 2022 Apr 22. pii: e71634. [Epub ahead of print]11
    A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
    James P Held, Gaomin Feng, Benjamin R Saunders, Claudia V Pereria, Kristopher Burkewitz, Maulik R Patel.
      The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.
    Keywords:  C. elegans; cell biology
    DOI:  https://doi.org/10.7554/eLife.71634
  4. Cell Death Dis. 2022 Apr 18. 13(4): 357
    Cancer cells adapt FAM134B/BiP mediated ER-phagy to survive hypoxic stress.
    Sandhya Chipurupalli, Raja Ganesan, Giulia Martini, Luigi Mele, Alessio Reggio, Marianna Esposito, Elango Kannan, Vigneshwaran Namasivayam, Paolo Grumati, Vincenzo Desiderio, Nirmal Robinson.
      In the tumor microenvironment, cancer cells experience hypoxia resulting in the accumulation of misfolded/unfolded proteins largely in the endoplasmic reticulum (ER). Consequently, ER proteotoxicity elicits unfolded protein response (UPR) as an adaptive mechanism to resolve ER stress. In addition to canonical UPR, proteotoxicity also stimulates the selective, autophagy-dependent, removal of discrete ER domains loaded with misfolded proteins to further alleviate ER stress. These mechanisms can favor cancer cell growth, metastasis, and long-term survival. Our investigations reveal that during hypoxia-induced ER stress, the ER-phagy receptor FAM134B targets damaged portions of ER into autophagosomes to restore ER homeostasis in cancer cells. Loss of FAM134B in breast cancer cells results in increased ER stress and reduced cell proliferation. Mechanistically, upon sensing hypoxia-induced proteotoxic stress, the ER chaperone BiP forms a complex with FAM134B and promotes ER-phagy. To prove the translational implication of our mechanistic findings, we identified vitexin as a pharmacological agent that disrupts FAM134B-BiP complex, inhibits ER-phagy, and potently suppresses breast cancer progression in vivo.
    DOI:  https://doi.org/10.1038/s41419-022-04813-w
  5. Biomolecules. 2022 Mar 23. pii: 487. [Epub ahead of print]12(4):
    Glycotherapy: A New Paradigm in Breast Cancer Research.
    Dipak K Banerjee, Arelis Seijo Lebrón, Krishna Baksi.
      Breast cancer is an ancient disease recognized first by the Egyptians as early as 1600 BC. The first cancer-causing gene in a chicken tumor virus was found in 1970. The United States signed the National Cancer Act in 1971, authorizing federal funding for cancer research. Irrespective of multi-disciplinary approaches, diverting a great deal of public and private resources, breast cancer remains at the forefront of human diseases, affecting as many as one in eight women during their lifetime. Because of overarching challenges and changes in the breast cancer landscape, five-year disease-free survival is no longer considered adequate. The absence of a cure, and the presence of drug resistance, severe side effects, and destruction of the patient's quality of life, as well as the fact that therapy is often expensive, making it unaffordable to many, have created anxiety among patients, families, and friends. One of the reasons for the failure of cancer therapeutics is that the approaches do not consider cancer holistically. Characteristically, all breast cancer cells and their microenvironmental capillary endothelial cells express asparagine-linked (N-linked) glycoproteins with diverse structures. We tested a small biological molecule, Tunicamycin, that blocks a specific step of the protein N-glycosylation pathway in the endoplasmic reticulum (ER), i.e., the catalytic activity of N-acetylglusosaminyl 1-phosphate transferase (GPT). The outcome was overwhelmingly exciting. Tunicamycin quantitatively inhibits angiogenesis in vitro and in vivo, and inhibits the breast tumor progression of multiple subtypes in pre-clinical mouse models with "zero" toxicity. Mechanistic details support ER stress-induced unfolded protein response (upr) signaling as the cause for the apoptotic death of both cancer and the microvascular endothelial cells. Additionally, it interferes with Wnt signaling. We therefore conclude that Tunicamycin can be expected to supersede the current therapeutics to become a glycotherapy for treating breast cancer of all subtypes.
    Keywords:  ER stress; N-acetylglucosaminyl 1-phosphate transferase; angiogenesis; asparagine-linked glycoprotein; breast cancer; glycotherapy; tunicamycin; unfolded protein response; upr
    DOI:  https://doi.org/10.3390/biom12040487
  6. Cell Death Dis. 2022 Apr 20. 13(4): 381
    Restoration of ER proteostasis attenuates remote apoptotic cell death after spinal cord injury by reducing autophagosome overload.
    Elisa Bisicchia, Roberta Mastrantonio, Annalisa Nobili, Claudia Palazzo, Livia La Barbera, Laura Latini, Francesco Millozzi, Valeria Sasso, Daniela Palacios, Marcello D'Amelio, Maria Teresa Viscomi.
      The pathogenic mechanisms that underlie the progression of remote degeneration after spinal cord injury (SCI) are not fully understood. In this study, we examined the relationship between endoplasmic reticulum (ER) stress and macroautophagy, hereafter autophagy, and its contribution to the secondary damage and outcomes that are associated with remote degeneration after SCI. Using a rat model of spinal cord hemisection at the cervical level, we measured ER stress and autophagy markers in the axotomized neurons of the red nucleus (RN). In SCI animals, mRNA and protein levels of markers of ER stress, such as GRP78, CHOP, and GADD34, increased 1 day after the injury, peaking on Day 5. Notably, in SCI animals, the increase of ER stress markers correlated with a blockade in autophagic flux, as evidenced by the increase in microtubule-associated protein 2 light chain 3 (LC3-II) and p62/SQSTM1 (p62) and the decline in LAMP1 and LAMP2 levels. After injury, treatment with guanabenz protected neurons from UPR failure and increased lysosomes biogenesis, unblocking autophagic flux. These effects correlated with greater activation of TFEB and improved neuronal survival and functional recovery-effects that persisted after suspension of the treatment. Collectively, our results demonstrate that in remote secondary damage, impairments in autophagic flux are intertwined with ER stress, an association that contributes to the apoptotic cell death and functional damage that are observed after SCI.
    DOI:  https://doi.org/10.1038/s41419-022-04830-9
  7. J Biol Chem. 2022 Apr 15. pii: S0021-9258(22)00375-1. [Epub ahead of print] 101935
    The mammalian rhomboid protein RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets.
    Viorica L Lastun, Clémence Levet, Matthew Freeman.
      In metazoans, the architecture of the endoplasmic reticulum (ER) differs between cell types, and undergoes major changes throughout the cell cycle and according to physiological needs. Although much is known about how the different ER morphologies are generated and maintained, especially ER tubules, how context-dependent changes in ER shape and distribution are regulated and the factors involved are less well characterized, as are the factors that contribute to the positioning of the ER within the cell. By overexpression and knockout experiments, we show that the levels of RHBDL4, an ER-resident rhomboid protease, modulate the shape and distribution of the ER, especially during conditions that require rapid changes in the ER sheet distribution, such as ER stress. We demonstrate that RHBDL4 interacts with CLIMP-63, a protein involved in ER sheet stabilisation, as well as with the cytoskeleton. Furthermore, we found that mice lacking RHBDL4 are sensitive to ER stress and develop liver steatosis, a phenotype associated with unresolved ER stress. Taken together, these data suggest a new physiological role for RHBDL4 and also imply that this function does not require its enzymatic activity.
    DOI:  https://doi.org/10.1016/j.jbc.2022.101935
  8. Oxid Med Cell Longev. 2022 ;2022 2531458
    Mitochondria-Endoplasmic Reticulum Contacts: The Promising Regulators in Diabetic Cardiomyopathy.
    Yan Chen, Yanguo Xin, Yue Cheng, Xiaojing Liu.
      Diabetic cardiomyopathy (DCM), as a serious complication of diabetes, causes structural and functional abnormalities of the heart and eventually progresses to heart failure. Currently, there is no specific treatment for DCM. Studies have proved that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are key factors for the development and progression of DCM. The mitochondria-associated ER membranes (MAMs) are a unique domain formed by physical contacts between mitochondria and ER and mediate organelle communication. Under high glucose conditions, changes in the distance and composition of MAMs lead to abnormal intracellular signal transduction, which will affect the physiological function of MAMs, such as alter the Ca2+ homeostasis in cardiomyocytes, and lead to mitochondrial dysfunction and abnormal apoptosis. Therefore, the dysfunction of MAMs is closely related to the pathogenesis of DCM. In this review, we summarized the evidence for the role of MAMs in DCM and described that MAMs participated directly or indirectly in the regulation of the pathophysiological process of DCM via the regulation of Ca2+ signaling, mitochondrial dynamics, ER stress, autophagy, and inflammation. Finally, we discussed the clinical transformation prospects and technical limitations of MAMs-associated proteins (such as MFN2, FUNDC1, and GSK3β) as potential therapeutic targets for DCM.
    DOI:  https://doi.org/10.1155/2022/2531458
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