bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒10‒13
seven papers selected by
Susan Logue
University of Manitoba
  1. Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma.
  2. Down-regulation of the islet-specific zinc transporter-8 (ZnT8) protects human insulinoma cells against inflammatory stress.
  3. Promotion of Axon Growth by the Secreted End of a Transcription Factor.
  4. The Increased RNase Activity of IRE1α in PBMCs from Patients with Rheumatoid Arthritis.
  5. Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress.
  6. UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis.
  7. Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14.
  1. Cancers (Basel). 2019 Oct 08. pii: E1502. [Epub ahead of print]11(10):
    Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma.
    Duo Xu, Haitang Yang, Zhang Yang, Sabina Berezowska, Yanyun Gao, Shun-Qing Liang, Thomas M Marti, Sean R R Hall, Patrick Dorn, Gregor J Kocher, Ralph A Schmid, Ren-Wang Peng.
      Malignant pleural mesothelioma (MPM) is a lethal cancer with limited treatment options. No targeted therapy has emerged yet. Here, we performed an integrated molecular characterization of patient tumors in the TCGA dataset, and discovered that endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR) signaling are characteristically deregulated in MPM. Consequently, pharmacological perturbation of ER stress/UPR axis by HA15, an agent that induces persistent proteotoxic stress in the ER, selectively suppresses the viability of MPM cells including those refractory to standard chemotherapy. Mechanically, HA15 augments the already high basal level of ER stress in MPM cells, embarks pro-apoptotic malfunctional UPR and autophagy, which eventually induces cell death in MPM. Importantly, HA15 exerts anti-MPM effectiveness in a mouse model of patient-derived xenografts (PDX) without eliciting overt toxicity when compared to chemotherapy. Our results revealed that programs orchestrating ER stress/UPR signaling represent therapeutic vulnerabilities in MPM and validate HA15 as a promising agent to treat patients with MPM, naïve or resistant to chemotherapy.
    Keywords:  HA15; autophagy; endoplasmic reticulum (ER) stress; malignant pleural mesothelioma (MPM); unfolded protein response (UPR)
    DOI:  https://doi.org/10.3390/cancers11101502
  2. J Biol Chem. 2019 Oct 07. pii: jbc.RA119.010937. [Epub ahead of print]
    Down-regulation of the islet-specific zinc transporter-8 (ZnT8) protects human insulinoma cells against inflammatory stress.
    Chengfeng Merriman, Dax Fu.
      Zinc transporter-8 (ZnT8) primarily functions as a zinc-sequestrating transporter in the insulin-secretory granules (ISGs) of pancreatic β cells. Loss-of-function mutations in ZnT8 are associated with protection against type-2 diabetes (T2D), but the protective mechanism is unclear. Here, we developed an in-cell ZnT8 assay to track endogenous ZnT8 responses to metabolic and inflammatory stresses applied to human insulinoma EndoC-βH1 cells. Unexpectedly, high glucose and free fatty acids (FFA) did not alter cellular ZnT8 levels, but proinflammatory cytokines acutely, reversibly, and gradually down-regulated ZnT8. Approximately 50% of the cellular ZnT8 was localized to the endoplasmic reticulum (ER), which was the primary target of the cytokine-mediated ZnT8 down-regulation. Transcriptome profiling of cytokine-exposed β cells revealed an adaptive unfolded protein response (UPR) including a marked immunoproteasome activation that coordinately degraded ZnT8 and insulin over a 1000-fold cytokine concentration range. RNAi-mediated ZnT8 knockdown protected cells against cytokine cytotoxicity whereas inhibiting immunoproteasomes blocked cytokine-induced ZnT8 degradation and triggered a transition of the adaptive UPR to cell apoptosis. Hence, cytokine-induced down-regulation of the ER ZnT8 level promotes adaptive UPR, acting as a protective mechanism that decongests the ER burden of ZnT8 to protect β cells from proapoptotic UPR during chronic low-grade inflammation.
    Keywords:  SLC30A8; Type 1 diabetes; Type 2 diabetes; ZnT8; cytokine; endoplasmic reticulum stress (ER stress); inflammation; insulin; pancreatic β-cells; solute carrier family 30 member 8; transport; transport metal; unfolded protein response (UPR); zinc
    DOI:  https://doi.org/10.1074/jbc.RA119.010937
  3. Cell Rep. 2019 Oct 08. pii: S2211-1247(19)31163-5. [Epub ahead of print]29(2): 363-377.e5
    Promotion of Axon Growth by the Secreted End of a Transcription Factor.
    Ethan P McCurdy, Kyung Min Chung, Carlos R Benitez-Agosto, Ulrich Hengst.
      Axon growth is regulated externally by attractive and repulsive cues generated in the environment. In addition, intrinsic pathways govern axon development, although the extent to which axons themselves can influence their own growth is unknown. We find that dorsal root ganglion (DRG) axons secrete a factor supporting axon growth and identify it as the C terminus of the ER stress-induced transcription factor CREB3L2, which is generated by site 2 protease (S2P) cleavage in sensory neurons. S2P and CREB3L2 knockdown or inhibition of axonal S2P interfere with the growth of axons, and C-terminal CREB3L2 is sufficient to rescue these effects. C-terminal CREB3L2 forms a complex with Shh and stabilizes its association with the Patched-1 receptor on developing axons. Our results reveal a neuron-intrinsic pathway downstream of S2P that promotes axon growth.
    Keywords:  CREB3L2; ER stress; OASIS transcription factors; S2P; Shh signaling; axon growth
    DOI:  https://doi.org/10.1016/j.celrep.2019.08.101
  4. Adv Pharm Bull. 2019 Aug;9(3): 505-509
    The Increased RNase Activity of IRE1α in PBMCs from Patients with Rheumatoid Arthritis.
    Mahdieh Ahmadiany, Mahshid Alavi-Samani, Zahra Hashemi, Mohammad Amin Moosavi, Marveh Rahmati.
      Purpose: Despite recent advances in the diagnosis and treatment of rheumatoid arthritis (RA), this inflammatory disease remains a challenge to patients and physicians. Recent evidence highlights the contribution of endoplasmic reticulum (ER) stress in the pathogenesis and treatment of RA. Herein, we study the expression of the ER stress sensor inositol-requiring enzyme 1α (IRE1α), as well as XBP1 splicing and the regulated IRE1-dependent decay (RIDD), in peripheral blood mononuclear cells (PBMCs) from patients with RA compared with healthy controls. Methods: The PBMCs from blood samples of RA patients and healthy volunteers were isolated by a density gradient centrifugation method using Ficoll. The gene expression levels of GRP78/ Bip, IRE1, XBP1s, micro-RNAs (miRNAs) were evaluated by real-time PCR. Results: The expression of GRP78, IRE1, and XBP1s were increased in PBMCs of RA patients compared with healthy controls. We further show that the RIDD targets (miRNA-17, -34a, -96, and -125b) were downregulated in RA samples. Conclusion: This study can expand our knowledge on the importance of RNase activity of IRE1α in RA and may offer new potentials for developing novel diagnostic and/or therapeutic biomarkers.
    Keywords:  Endoplasmic reticulum stress; IRE1-dependent decay; Inositol-requiring enzyme 1; Rheumatoid arthritis; microRNA
    DOI:  https://doi.org/10.15171/apb.2019.060
  5. Elife. 2019 Oct 10. pii: e49796. [Epub ahead of print]8
    Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress.
    Abigail Buchwalter, Roberta Schulte, Hsiao Tsai, Juliana Capitanio, Martin Hetzer.
      The inner nuclear membrane (INM) is a subdomain of the endoplasmic reticulum (ER) that is gated by the nuclear pore complex. It is unknown whether proteins of the INM and ER are degraded through shared or distinct pathways in mammalian cells. We applied dynamic proteomics to profile protein half-lives and report that INM and ER residents turn over at similar rates, indicating that the INM's unique topology is not a barrier to turnover. Using a microscopy approach, we observed that the proteasome can degrade INM proteins in situ. However, we also uncovered evidence for selective, vesicular transport-mediated turnover of a single INM protein, emerin, that is potentiated by ER stress. Emerin is rapidly cleared from the INM by a mechanism that requires emerin's LEM domain to mediate vesicular trafficking to lysosomes. This work demonstrates that the INM can be dynamically remodeled in response to environmental inputs.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.49796
  6. Cell Res. 2019 Oct 08.
    UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis.
    Lihui Wang, Yue Xu, Heather Rogers, Layla Saidi, Constance Tom Noguchi, Honglin Li, Jonathan Wilson Yewdell, Nicholas Raymond Guydosh, Yihong Ye.
      Protein biogenesis at the endoplasmic reticulum (ER) in eukaryotic cells is monitored by a protein quality control system named ER-associated protein degradation (ERAD). While there has been substantial progress in understanding how ERAD eliminates defective polypeptides generated from erroneous folding, how cells remove nascent chains stalled in the translocon during co-translational protein insertion into the ER is unclear. Here we show that ribosome stalling during protein translocation induces the attachment of UFM1, a ubiquitin-like modifier, to two conserved lysine residues near the COOH-terminus of the 60S ribosomal subunit RPL26 (uL24) at the ER. Strikingly, RPL26 UFMylation enables the degradation of stalled nascent chains, but unlike ERAD or previously established cytosolic ribosome-associated quality control (RQC), which uses proteasome to degrade their client proteins, ribosome UFMylation promotes the targeting of a translocation-arrested ER protein to lysosomes for degradation. RPL26 UFMylation is upregulated during erythroid differentiation to cope with increased secretory flow, and compromising UFMylation impairs protein secretion, and ultimately hemoglobin production. We propose that in metazoan, co-translational protein translocation into the ER is safeguarded by a UFMylation-dependent protein quality control mechanism, which when impaired causes anemia in mice and abnormal neuronal development in humans.
    DOI:  https://doi.org/10.1038/s41422-019-0236-6
  7. Proc Natl Acad Sci U S A. 2019 Oct 08. pii: 201907288. [Epub ahead of print]
    Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14.
    Bin Liu, Zhijian Zhang, Yanyun Hu, Yan Lu, Duanzhuo Li, Jie Liu, Shengjie Liao, Min Hu, Yuxing Wang, Die Zhang, Yulu Chen, Qilan Qian, Xianfeng Lv, Duojiao Wu, Minjia Tan, Cheng Hu, Xuelian Xiong, Xiaoying Li.
      Endoplasmic reticulum (ER) stress plays an important role in metabolic diseases like obesity and type 2 diabetes mellitus (T2DM), although the underlying mechanisms and regulatory pathways remain to be elucidated. Here, we induced chronic low-grade ER stress in lean mice to levels similar to those in high-fat diet (HFD)-fed obese mice and found that it promoted hyperglycemia due to enhanced hepatic gluconeogenesis. Mechanistically, sustained ER stress up-regulated the deubiquitinating enzyme ubiquitin-specific peptidase 14 (USP14), which increased the stability and levels of 3',5'-cyclic monophosphate-responsive element binding (CREB) protein (CBP) to enhance glucagon action and hepatic gluconeogenesis. Exogenous overexpression of USP14 in the liver significantly increased hepatic glucose output. Consistent with this, liver-specific knockdown of USP14 abrogated the effects of ER stress on glucose metabolism, and also improved hyperglycemia and glucose intolerance in obese mice. In conclusion, our findings show a mechanism underlying ER stress-induced disruption of glucose homeostasis, and present USP14 as a potential therapeutic target against T2DM.
    Keywords:  ER stress; USP14; gluconeogenesis; hepatic glucose production; type 2 diabetes
    DOI:  https://doi.org/10.1073/pnas.1907288116
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:25:05.