bims-unfpre 2019-06-02 papers

Issue of 2019–06–02
five papers selected by
Susan Logue, University of Manitoba

Elife. 2019 May 31. pii: e46595. [Epub ahead of print]8

Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether.

Sandra Elizabeth Torres, Ciara M Gallagher, Lars Plate, Meghna Gupta, Christina R Liem, Xiaoyan Guo, Ruilin Tian, Robert M Stroud, Martin Kampmann, Jonathan S Weissman, Peter Walter.

The unfolded protein response (UPR) detects and restores deficits in the endoplasmic reticulum (ER) protein folding capacity. Ceapins specifically inhibit the UPR sensor ATF6α, an ER-tethered transcription factor, by retaining it at the ER through an unknown mechanism. Our genome-wide CRISPR interference (CRISPRi) screen reveals that Ceapins function is completely dependent on the ABCD3 peroxisomal transporter. Proteomics studies establish that ABCD3 physically associates with ER-resident ATF6α in cells and in vitro in a Ceapin-dependent manner. Ceapins induce the neomorphic association of ER and peroxisomes by directly tethering the cytosolic domain of ATF6α to ABCD3's transmembrane regions without inhibiting or depending on ABCD3 transporter activity. Thus, our studies reveal that Ceapins function by chemical-induced misdirection which explains their remarkable specificity and opens up new mechanistic routes for drug development and synthetic biology.

Keywords: biochemistry; cell biology; chemical biology; human

DOI: https://doi.org/10.7554/eLife.46595

Cell Stress Chaperones. 2019 May 30.

The endoplasmic reticulum unfolded protein response varies depending on the affected region of the tissue but independently from the source of stress.

Jessica Perochon, Benjamin Grandon, Delphine Roche, Christine Wintz, Yohan Demay, Bernard Mignotte, Sébastien Szuplewski, Sébastien Gaumer.

Accumulation of unfolded proteins and calcium dyshomeostasis induces endoplasmic reticulum (ER) stress, which can be resolved by the unfolded protein response (UPR). We have previously reported that activation of the PERK/ATF4 branch of the UPR, by overexpressing Presenilin in part of the vestigial domain of Drosophila wing imaginal discs, induces both a caspase-dependent apoptosis and a Slpr/JNK/Dilp8-dependent developmental delay that allows compensation of cell death in the tissue. Recently, dDad1 depletion in Drosophila in engrailed-expressing cells of wing imaginal discs was also reported to activate the PERK/ATF4 branch but induced Mekk1/JNK-dependent apoptosis. Here, we assessed whether the stressed cell location in the wing imaginal disc could explain these differences in response to chronic ER stress or whether the stress source could be responsible for the signaling discrepancy. To address this question, we overexpressed a Rhodopsin-1 mutant prone to aggregate either in vestigial- or engrailed-expressing cells. We observed similar responses to the Presenilin overexpression in the vestigial domain and to the dDad1 depletion in the engrailed domain. Therefore, the consequences of a PERK/ATF4 branch activation depend on the position of the cell in the Drosophila wing imaginal disc, suggesting interactions of PERK signaling with developmental pathways involved in the determination or maintenance of wing domains.

Keywords: Apoptosis; Homeostasis; PERK; UPR; Wing imaginal disc

DOI: https://doi.org/10.1007/s12192-019-01009-8

J Comp Neurol. 2019 May 27.

Profile of the Unfolded Protein Response in Rat Cerebellar Cortical Development.

Michelle Naughton, Sinead Healy, Jill McMahon, Una FitzGerald.

The unfolded protein response (UPR) has been reported during normal development of cortical neurons and cerebellar white matter and may also contribute to the pathogenesis of neurological conditions, such as Marinesco-Sjogren syndrome and Borna virus infection, which result in cerebellar defects. The UPR is initiated when the processing capacity of the endoplasmic reticulum (ER) is overwhelmed. Misfolded proteins accumulate and can activate ER stress sensors; PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), activated transcription factor 6 (ATF6) and their downstream targets glucose-regulated protein 78 (GRP78), glucose-regulated protein 94 (GRP94) and protein disulphide isomerase (PDI). In order to provide a fuller appreciation of the possible importance of ER stress-associated proteins in the context of cerebellar disease, we have profiled the expression of ER stress sensors and their downstream targets in the developing cerebellar cortex in postnatal rat. Activation of PERK and IRE1 stress sensors was observed for the first time in normally developing granule cell precursors. A second proliferative pPERK-positive population was also detected in the internal granular layer (IGL). In general, the density of UPR protein-positive cells was found to decrease significantly when profiles in early and late postnatal ages were compared. These data may be relevant to studies of medulloblastoma and warrant further investigation. This article is protected by copyright. All rights reserved.

Keywords: ATF6; GRP78; GRP94; PDI; RRID:AB_10145203; RRID:AB_144696; RRID:AB_2089254; RRID:AB_2156433; RRID:AB_2293243; RRID:AB_2687571; RRID:AB_477010; RRID:AB_725571; RRID:AB_732737; RRID:AB_823506; UPR; cerebellar cortex; cerebellar cortical development; endoplasmic reticulum stress; external granular layer; granule cell precursor; internal granular layer; medulloblastoma; neonatal cerebellum; neural precursor cell; pIRE1; pPERK; perinatal white matter; unfolded protein response

DOI: https://doi.org/10.1002/cne.24718

Mol Cell Biol. 2019 May 28. pii: MCB.00184-19. [Epub ahead of print]

TLR/MyD88/XBP1 signaling axis mediates skeletal muscle wasting during cancer cachexia.

Kyle R Bohnert, Praneeth Goli, Anirban Roy, Aditya K Sharma, Guangyan Xiong, Yann S Gallot, Ashok Kumar.

Skeletal muscle wasting causes both morbidity and mortality of cancer patients. Accumulating evidence suggests that the markers of ER stress and unfolded protein response (UPR) pathways are increased in skeletal muscle in multiple catabolic conditions, including cancer. However, signaling mechanisms and the role of individual arms of the UPR in the regulation of skeletal muscle mass remain largely unknown. In the present study, we demonstrate that the gene expression of Toll-like receptors (TLRs) and MyD88 is increased in skeletal muscle of Lewis lung carcinoma (LLC) model of cancer cachexia. Targeted ablation of MyD88 inhibits the loss of skeletal muscle mass and strength in LLC tumor-bearing mice. Inhibition of MyD88 attenuates the LLC-induced activation of the UPR in skeletal muscle of mice. Moreover, muscle-specific deletion of X-box binding protein 1 (XBP1), a major downstream target of IRE1α arm of the UPR, ameliorates muscle wasting in LLC tumor-bearing mice. Our results also demonstrate that overexpression of an active form of XBP1 causes atrophy in cultured myotubes. By contrast, knockdown of XBP1 inhibits myotube atrophy in response to LLC or C26 adenocarcinoma cells conditioned medium. Collectively, our results demonstrate that the TLR/MyD88-mediated activation of XBP1 causes skeletal muscle wasting in LLC tumor-bearing mice.

DOI: https://doi.org/10.1128/MCB.00184-19

Cell Death Dis. 2019 May 28. 10(6): 418

Inhibition of eIF2α dephosphorylation accelerates pterostilbene-induced cell death in human hepatocellular carcinoma cells in an ER stress and autophagy-dependent manner.

Chen-Lin Yu, Shun-Fa Yang, Tung-Wei Hung, Chia-Liang Lin, Yi-Hsien Hsieh, Hui-Ling Chiou.

Hepatocellular carcinoma (HCC) is the one of the most common cancers worldwide. Because the side effects of current treatments are severe, new effective therapeutic strategies are urgently required. Pterostilbene (PT), a natural analogue of resveratrol, has diverse pharmacologic activities, including antioxidative, anti-inflammatory and antiproliferative activities. Here we demonstrated that PT inhibits HCC cell growth without the induction of apoptosis in an endoplasmic reticulum (ER) stress- and autophagy-dependent manner. Mechanistic studies indicated that the combination of salubrinal and PT modulates ER stress-related autophagy through the phospho-eukaryotic initiation factor 2α/activating transcription factor-4/LC3 pathway, leading to a further inhibition of eIF2α dephosphorylation and the potentiation of cell death. An in vivo xenograft analysis revealed that PT significantly reduced tumour growth in mice with a SK-Hep-1 tumour xenograft. Taken together, our results yield novel insights into the pivotal roles of PT in ER stress- and autophagy-dependent cell death in HCC cells.

DOI: https://doi.org/10.1038/s41419-019-1639-5