bims-unfpre 2022-10-02 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022‒10‒02
eight papers selected by
Susan Logue
University of Manitoba

ER stress transforms random olfactory receptor choice into axon targeting precision.
Hepatic ER stress suppresses adipose browning through ATF4-CIRP-ANGPTL3 cascade.
MFN2 mediates ER-mitochondrial coupling during ER stress through specialized stable contact sites.
ER stress promotes mitochondrial DNA mediated type-1 interferon response in beta-cells and interleukin-8 driven neutrophil chemotaxis.
Glabridin induces paraptosis-like cell death via ER stress in breast cancer cells.
A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress.
The endoplasmic reticulum stress response in prostate cancer.
Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations.

Cell. 2022 Sep 21. pii: S0092-8674(22)01120-5. [Epub ahead of print]

ER stress transforms random olfactory receptor choice into axon targeting precision.

Hani J Shayya, Jerome K Kahiapo, Rachel Duffié, Katherine S Lehmann, Lisa Bashkirova, Kevin Monahan, Ryan P Dalton, Joanna Gao, Song Jiao, Ira Schieren, Leonardo Belluscio, Stavros Lomvardas.

  Olfactory sensory neurons (OSNs) convert the stochastic choice of one of >1,000 olfactory receptor (OR) genes into precise and stereotyped axon targeting of OR-specific glomeruli in the olfactory bulb. Here, we show that the PERK arm of the unfolded protein response (UPR) regulates both the glomerular coalescence of like axons and the specificity of their projections. Subtle differences in OR protein sequences lead to distinct patterns of endoplasmic reticulum (ER) stress during OSN development, converting OR identity into distinct gene expression signatures. We identify the transcription factor Ddit3 as a key effector of PERK signaling that maps OR-dependent ER stress patterns to the transcriptional regulation of axon guidance and cell-adhesion genes, instructing targeting precision. Our results extend the known functions of the UPR from a quality-control pathway that protects cells from misfolded proteins to a sensor of cellular identity that interprets physiological states to direct axon wiring.

Keywords:  Ddit3; PERK; axon guidance; axon targeting; cell adhesion; extracellular barcodes; olfactory receptors; stochastic gene choice; transcriptional networks; unfolded protein response

DOI:  https://doi.org/10.1016/j.cell.2022.08.025
Cell Rep. 2022 Sep 27. pii: S2211-1247(22)01263-3. [Epub ahead of print]40(13): 111422

Hepatic ER stress suppresses adipose browning through ATF4-CIRP-ANGPTL3 cascade.

Sihan Lv, Yingqun Zhou, Jiaojiao Chen, Huiwen Yuan, Zhen-Ning Zhang, Bing Luan.

  Hepatic endoplasmic reticulum (ER) stress is a hallmark of obesity-induced liver steatosis and contributes to the progress of steatosis and insulin resistance in liver. However, its influence on adipose function is still unclear. Here, we identify a hepatic ER stress-induced activating transcription factor 4 (ATF4)-cold-inducible RNA-binding protein (CIRP)-angiopoietin-related protein3 (ANGPTL3) cascade critical for the regulation of adipose browning. We find that obesity increases CIRP expression in liver through ER stress-induced ATF4. CIRP in turn binds to the 3' UTR and increases mRNA stability of ANGPTL3. ANGPTL3 secreted from liver suppresses uncoupling protein 1 expression through integrin αvβ3 and c-Jun N-terminal kinase in adipose tissue. While hepatic expression of either ATF4, CIRP, or ANGPTL3 suppresses adipose browning, knockdown of CIRP and ANGPTL3 in liver or administration of integrin αvβ3 inhibitor cilengitide increases adipose browning process. Taken together, we identify a communication mechanism to link hepatic ER stress and adipose browning that may imply a reciprocal regulation of obesity and liver steatosis.

Keywords:  ANGPTL3; ATF4; CIRP; CP: Metabolism; adipose browning; hepatic ER stress

DOI:  https://doi.org/10.1016/j.celrep.2022.111422
Front Cell Dev Biol. 2022 ;10 918691

MFN2 mediates ER-mitochondrial coupling during ER stress through specialized stable contact sites.

Benjamin Gottschalk, Zhanat Koshenov, Olaf A Bachkoenig, René Rost, Roland Malli, Wolfgang F Graier.

  Endoplasmic reticulum (ER) functions critically depend on a suitable ATP supply to fuel ER chaperons and protein trafficking. A disruption of the ability of the ER to traffic and fold proteins leads to ER stress and the unfolded protein response (UPR). Using structured illumination super-resolution microscopy, we revealed increased stability and lifetime of mitochondrial associated ER membranes (MAM) during ER stress. The consequent increase of basal mitochondrial Ca2+ leads to increased TCA cycle activity and enhanced mitochondrial membrane potential, OXPHOS, and ATP generation during ER stress. Subsequently, OXPHOS derived ATP trafficking towards the ER was increased. We found that the increased lifetime and stability of MAMs during ER stress depended on the mitochondrial fusion protein Mitofusin2 (MFN2). Knockdown of MFN2 blunted mitochondrial Ca2+ effect during ER stress, switched mitochondrial F1FO-ATPase activity into reverse mode, and strongly reduced the ATP supply for the ER during ER stress. These findings suggest a critical role of MFN2-dependent MAM stability and lifetime during ER stress to compensate UPR by strengthening ER ATP supply by the mitochondria.

Keywords:  ER stress; mitochondria; mitochondria-associated membranes (MAM); mitochondrial Ca2+; mitofusin 2

DOI:  https://doi.org/10.3389/fcell.2022.918691
Front Endocrinol (Lausanne). 2022 ;13 991632

ER stress promotes mitochondrial DNA mediated type-1 interferon response in beta-cells and interleukin-8 driven neutrophil chemotaxis.

Saurabh Vig, Joost M Lambooij, Mette C Dekkers, Frank Otto, Françoise Carlotti, Bruno Guigas, Arnaud Zaldumbide.

  Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. Accumulating evidence suggests the engagement of cellular stress during the initial stage of the disease, preceding destruction and triggering immune cell infiltration. While the role of the endoplasmic reticulum (ER) in this process has been largely described, the participation of the other cellular organelles, particularly the mitochondria which are central mediator for beta-cell survival and function, remains poorly investigated. Here, we have explored the contribution of ER stress, in activating type-I interferon signaling and innate immune cell recruitment. Using human beta-cell line EndoC-βH1 exposed to thapsigargin, we demonstrate that induction of cellular stress correlates with mitochondria dysfunction and a significant accumulation of cytosolic mitochondrial DNA (mtDNA) that triggers neutrophils migration by an IL8-dependent mechanism. These results provide a novel mechanistic insight on how ER stress can cause insulitis and may ultimately facilitate the identification of potential targets to protect beta-cells against immune infiltration.

Keywords:  ER stress; innate immunity; mitochondria; neutrophils; type 1 diabetes

DOI:  https://doi.org/10.3389/fendo.2022.991632
Heliyon. 2022 Sep;8(9): e10607

Glabridin induces paraptosis-like cell death via ER stress in breast cancer cells.

Xiang Cui, Min Cui.

  Glabridin, a polyphenolic flavonoid isolated from the root of the glycyrrhiza glabra, has been demonstrated to have anti-tumor properties in human malignancies. This study found that glabridin decreased the viability of human breast cancer MDA-MB-231 and MCF7 cells in a dose-dependent manner that was not involved in the caspase-3 cascade. Glabridin promoted the formation of extensive cytoplasmic vacuolation by increasing the expression of endoplasmic reticulum (ER) stress markers BiP, XBP1s, and CHOP. The transmission electron microscopy and fluorescence with the ER chaperon KDEL suggested that the vacuoles were derived from ER. Glabridin-induced vacuolation was blocked when protein synthesis was inhibited by cycloheximide, demonstrating that protein synthesis is crucial for this process. Furthermore, we determined that glabridin causes loss of mitochondrial membrane potential as well as the production of reactive oxygen species, both of which lead to mitochondrial dysfunction. These features are consistent with a kind of programmed cell death described as paraptosis. This work reports for the first time that glabridin could induce paraptosis-like cell death, which may give new therapeutic approaches for apoptosis-resistant breast cancers.

Keywords:  Breast cancer; ER stress; Glabridin; Paraptosis; Vacuolation

DOI:  https://doi.org/10.1016/j.heliyon.2022.e10607
PLoS Genet. 2022 Sep 27. 18(9): e1010430

A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress.

Hans M Dalton, Raghuvir Viswanatha, Roderick Brathwaite, Jae Sophia Zuno, Alexys R Berman, Rebekah Rushforth, Stephanie E Mohr, Norbert Perrimon, Clement Y Chow.

Partial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually causes CDGs. While both in vivo models ostensibly cause cellular stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress.

DOI: https://doi.org/10.1371/journal.pgen.1010430
Nat Rev Urol. 2022 Sep 27.

The endoplasmic reticulum stress response in prostate cancer.

Claire M de la Calle, Kevin Shee, Heiko Yang, Peter E Lonergan, Hao G Nguyen.

In order to proliferate in unfavourable conditions, cancer cells can take advantage of the naturally occurring endoplasmic reticulum-associated unfolded protein response (UPR) via three highly conserved signalling arms: IRE1α, PERK and ATF6. All three arms of the UPR have key roles in every step of tumour progression: from cancer initiation to tumour growth, invasion, metastasis and resistance to therapy. At present, no cure for metastatic prostate cancer exists, as targeting the androgen receptor eventually results in treatment resistance. New research has uncovered an important role for the UPR in prostate cancer tumorigenesis and crosstalk between the UPR and androgen receptor signalling pathways. With an improved understanding of the mechanisms by which cancer cells exploit the endoplasmic reticulum stress response, targetable points of vulnerability can be uncovered.

DOI: https://doi.org/10.1038/s41585-022-00649-3
Neoplasia. 2022 Nov;pii: S1476-5586(22)00063-X. [Epub ahead of print]33 100837

Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations.

Dat P Ha, Bo Huang, Han Wang, Daisy Flores Rangel, Richard Van Krieken, Ze Liu, Soma Samanta, Nouri Neamati, Amy S Lee.

  KRAS is the most commonly mutated oncogene in human cancers with limited therapeutic options, thus there is a critical need to identify novel targets and inhibiting agents. The 78-kDa glucose-regulated protein GRP78, which is upregulated in KRAS cancers, is an essential chaperone and the master regulator of the unfolded protein response (UPR). Following up on our recent discoveries that GRP78 haploinsufficiency suppresses both KRASG12D-driven pancreatic and lung tumorigenesis, we seek to determine the underlying mechanisms. Here, we report that knockdown of GRP78 via siRNA reduced oncogenic KRAS protein level in human lung, colon, and pancreatic cancer cells bearing various KRAS mutations. This effect was at the post-transcriptional level and is independent of proteasomal degradation or autophagy. Moreover, targeting GRP78 via small molecule inhibitors such as HA15 and YUM70 with anti-cancer activities while sparing normal cells significantly suppressed oncogenic KRAS expression in vitro and in vivo, associating with onset of apoptosis and loss of viability in cancer cells bearing various KRAS mutations. Collectively, our studies reveal that GRP78 is a previously unidentified regulator of oncogenic KRAS expression, and, as such, augments the other anti-cancer activities of GRP78 small molecule inhibitors to potentially achieve general, long-term suppression of mutant KRAS-driven tumorigenesis.

Keywords:  Colon cancer; GRP78; KRAS; Lung cancer; Pancreatic cancer; Small molecule inhibitors

DOI:  https://doi.org/10.1016/j.neo.2022.100837