bims-unfpre 2020-08-02 papers

Issue of 2020‒08‒02
six papers selected by
Susan Logue
University of Manitoba

Cell Calcium. 2020 Jul 17. pii: S0143-4160(20)30091-9. [Epub ahead of print]91 102249

Getting intimate: Lysosomes and ER rendezvous to control autophagy.

The endoplasmic reticulum (ER) is the source of lysosomal calcium. The finding that the protein TMBIM6 -a putative ER calcium channel and cell death regulator -promotes calcium transfer from the ER to lysosomes to induce autophagy uncovers a missing piece in the puzzle of inter-organelle communication.

Keywords: Autophagy; Calcium; ER stress; Lysosome; Protein misfolding; UPR

DOI: https://doi.org/10.1016/j.ceca.2020.102249

Mol Cell. 2020 Jul 28. pii: S1097-2765(20)30510-4. [Epub ahead of print]

A UPR-Induced Soluble ER-Phagy Receptor Acts with VAPs to Confer ER Stress Resistance.

Dan Zhao, Chen-Xi Zou, Xiao-Man Liu, Zhao-Di Jiang, Zhong-Qiu Yu, Fang Suo, Tong-Yang Du, Meng-Qiu Dong, Wanzhong He, Li-Lin Du.

Autophagic degradation of the endoplasmic reticulum (ER-phagy) is triggered by ER stress in diverse organisms. However, molecular mechanisms governing ER stress-induced ER-phagy remain insufficiently understood. Here we report that ER stress-induced ER-phagy in the fission yeast Schizosaccharomyces pombe requires Epr1, a soluble Atg8-interacting ER-phagy receptor. Epr1 localizes to the ER through interacting with integral ER membrane proteins VAPs. Bridging an Atg8-VAP association is the main ER-phagy role of Epr1, as it can be bypassed by an artificial Atg8-VAP tether. VAPs contribute to ER-phagy not only by tethering Atg8 to the ER membrane, but also by maintaining the ER-plasma membrane contact. Epr1 is upregulated during ER stress by the unfolded protein response (UPR) regulator Ire1. Loss of Epr1 reduces survival against ER stress. Conversely, increasing Epr1 expression suppresses the ER-phagy defect and ER stress sensitivity of cells lacking Ire1. Our findings expand and deepen the molecular understanding of ER-phagy.

Keywords: ER stress; ER-phagy; ER-plasma membrane contact; UPR; autophagy; autophagy receptor

DOI: https://doi.org/10.1016/j.molcel.2020.07.019

Elife. 2020 Jul 28. pii: e55596. [Epub ahead of print]9

Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation.

Antonio Galeone, Joshua M Adams, Shinya Matsuda, Maximiliano F Presa, Ashutosh Pandey, Seung Yeop Han, Yuriko Tachida, Hiroto Hirayama, Thomas Vaccari, Tadashi Suzuki, Cathleen M Lutz, Markus Affolter, Aamir Zuberi, Hamed Jafar-Nejad.

During endoplasmic reticulum-associated degradation (ERAD), the cytoplasmic enzyme N-glycanase 1 (NGLY1) is proposed to remove N-glycans from misfolded N-glycoproteins after their retrotranslocation from the ER to the cytosol. We previously reported that NGLY1 regulates Drosophila BMP signaling in a tissue-specific manner (Galeone et al., 2017). Here, we establish the Drosophila Dpp and its mouse ortholog BMP4 as biologically relevant targets of NGLY1 and find, unexpectedly, that NGLY1-mediated deglycosylation of misfolded BMP4 is required for its retrotranslocation. Accumulation of misfolded BMP4 in the ER results in ER stress and prompts the ER recruitment of NGLY1. The ER-associated NGLY1 then deglycosylates misfolded BMP4 molecules to promote their retrotranslocation and proteasomal degradation, thereby allowing properly-folded BMP4 molecules to proceed through the secretory pathway and activate signaling in other cells. Our study redefines the role of NGLY1 during ERAD and suggests that impaired BMP4 signaling might underlie some of the NGLY1 deficiency patient phenotypes.

Keywords: BMP signaling; D. melanogaster; ERAD; N-glycosylation; NGLY1; cell biology; deglycosylation; developmental biology; mouse; retrotranslocation

DOI: https://doi.org/10.7554/eLife.55596

Sci Rep. 2020 Jul 28. 10(1): 12620

Cigarette smoke induces endoplasmic reticulum stress and suppresses efferocytosis through the activation of RhoA.

Hiroyuki Ito, Yoshiro Yamashita, Takeshi Tanaka, Masahiro Takaki, Minh Nhat Le, Lay-Myint Yoshida, Konosuke Morimoto.

Impaired efferocytosis is a key mechanism of inflammatory lung diseases, including chronic obstructive pulmonary disease and cystic fibrosis. Cigarette smoking activates RhoA and impairs efferocytosis in alveolar macrophages, but the mechanism has not been fully elucidated. We investigated the role of endoplasmic reticulum (ER) stress induced by cigarette smoking in the disruption of efferocytosis. Both tunicamycin (10 μg/ml) and thapsigargin (0.1 and 1 μM), which are ER stress inducers, suppressed efferocytosis in J774 cells, and a Rho-associated coiled-coil-forming kinase (ROCK) inhibitor (Y27632) reversed this effect. We validated the effect of tunicamycin on efferocytosis in experiments using RAW264.7 cells. Then, we investigated the role of the unfolded protein response (UPR) in efferocytosis impaired by ER stress. A PERK inhibitor (GSK2606414) restored the efferocytosis that had been impaired by TM, and an eIF2α dephosphorylation inhibitor (salubrinal) suppressed efferocytosis. Cigarette smoke extract (CSE) induced ER stress in J774 macrophages and RhoA activation in J774 cells, and the CSE-induced ROCK activity was successfully reversed by GSK2606414 and tauroursodeoxycholic acid. Finally, we confirmed that ER stress suppresses efferocytosis in murine alveolar macrophages and that GSK2606414 could rescue this process. These data suggest that cigarette smoke-induced ER stress and the UPR play crucial roles in RhoA activation and suppression of efferocytosis in the lung.

DOI: https://doi.org/10.1038/s41598-020-69610-x

Cell Death Dis. 2020 Jul 27. 11(7): 582

Ciclopirox activates PERK-dependent endoplasmic reticulum stress to drive cell death in colorectal cancer.

Jianjun Qi, Ningning Zhou, Liyi Li, Shouyong Mo, Yidan Zhou, Yao Deng, Ting Chen, Changliang Shan, Qin Chen, Bin Lu.

Ciclopirox (CPX) modulates multiple cellular pathways involved in the growth of a variety of tumor cell types. However, the effects of CPX on colorectal cancer (CRC) and the underlying mechanisms for its antitumor activity remain unclear. Herein, we report that CPX exhibited strong antitumorigenic properties in CRC by inducing cell cycle arrest, repressing cell migration, and invasion by affecting N-cadherin, Snail, E-cadherin, MMP-2, and MMP-9 expression, and disruption of cellular bioenergetics contributed to CPX-associated inhibition of cell growth, migration, and invasion. Interestingly, CPX-induced reactive oxygen species (ROS) production and impaired mitochondrial respiration, whereas the capacity of glycolysis was increased. CPX (20 mg/kg, intraperitoneally) substantially inhibited CRC xenograft growth in vivo. Mechanistic studies revealed that the antitumor activity of CPX relies on apoptosis induced by ROS-mediated endoplasmic reticulum (ER) stress in both 5-FU-sensitive and -resistant CRC cells. Our data reveal a novel mechanism for CPX through the disruption of cellular bioenergetics and activating protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent ER stress to drive cell death and overcome drug resistance in CRC, indicating that CPX could potentially be a novel chemotherapeutic for the treatment of CRC.

DOI: https://doi.org/10.1038/s41419-020-02779-1

J Biol Chem. 2020 07 28. pii: jbc.RA120.014307. [Epub ahead of print]

CHOP and c-JUN upregulate the mutant Z alpha-1 antitrypsin, exacerbating its aggregation and liver proteotoxicity.

Sergio Attanasio, Rosa Ferriero, Gwladys Gernoux, Rossella De Cegli, Annamaria Carissimo, Edoardo Nusco, Severo Campione, Jeffrey Teckman, Christian Mueller, Pasquale Piccolo, Nicola Brunetti-Pierri.

Alpha-1 antitrypsin (AAT) encoded by SERPINA1 gene is an acute phase protein synthesized in the liver and secreted into the circulation. Its primary role is to protect lung tissue by inhibiting neutrophil elastase. The Z allele of SERPINA1 encodes a mutant AAT, known as ATZ, that changes the protein structure and leads to its misfolding and polymerization that cause endoplasmic reticulum (ER) stress and liver disease through a gain-of-function toxic mechanism. Hepatic retention of ATZ results in deficiency of one of the most important circulating proteinase inhibitors and predisposes to early-onset emphysema through a loss-of-function mechanism. The pathogenetic mechanisms underlying the liver disease are not completely understood. C/EBP homologous protein (CHOP), a transcription factor induced by ER stress, was found among the most upregulated genes in PiZ mice that express ATZ, and in human livers of patients homozygous for the Z allele. Compared to controls, juvenile PiZ/Chop-/- mice showed reduced hepatic ATZ and a transcriptional response indicative of decreased ER stress by RNA-seq analysis. Livers of PiZ/Chop-/- mice also showed reduced SERPINA1 mRNA levels. By chromatin immunoprecipitations and luciferase reporter-based transfection assays, CHOP was found to upregulate SERPINA1 cooperating with c-JUN, that was previously shown to upregulate SERPINA1, thus aggravating hepatic accumulation of ATZ. Increased CHOP levels were detected in diseased livers of children homozygous for the Z allele. In summary, CHOP and c-JUN upregulates SERPINA1 transcription and play an important role in the hepatic disease by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.

Keywords: alpha1 antitrypsin; c-Jun transcription factor; liver; liver injury; serpin; transcription regulation

DOI: https://doi.org/10.1074/jbc.RA120.014307