bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021–07–18
eleven papers selected by
Susan Logue, University of Manitoba
  1. A role for the ribosome-associated complex in activation of the IRE1 branch of UPR.
  2. Recruitment of endoplasmic reticulum-targeted and cytosolic mRNAs into membrane-associated stress granules.
  3. Unfolded protein response during cardiovascular disorders: a tilt towards pro-survival and cellular homeostasis.
  4. Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans.
  5. Integration of Metabolomics and Transcriptomics Reveals Ketone Body and Lipid Metabolism Disturbance Related to ER Stress in the Liver.
  6. The role of Ire1 in Drosophila eye pigmentation revealed by an RNase dead allele.
  7. Effect of the mitochondrial unfolded protein response on hypoxic death and mitochondrial protein aggregation.
  8. On the offense and defense: mitochondrial recovery programs amidst targeted pathogenic assault.
  9. ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease.
  10. Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis.
  11. miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer.
  1. Cell Rep. 2021 Jul 13. pii: S2211-1247(21)00764-6. [Epub ahead of print]36(2): 109366
    A role for the ribosome-associated complex in activation of the IRE1 branch of UPR.
    I-Hui Wu, Jae Seok Yoon, Qian Yang, Yi Liu, William Skach, Philip Thomas.
      
    DOI:  https://doi.org/10.1016/j.celrep.2021.109366
  2. RNA. 2021 Jul 08. pii: rna.078858.121. [Epub ahead of print]
    Recruitment of endoplasmic reticulum-targeted and cytosolic mRNAs into membrane-associated stress granules.
    Jessica Rae Child, Qiang Chen, David W Reid, Sujatha Jagannathan, Christopher Nicchitta.
      Stress granules (SGs) are membraneless organelles composed of mRNAs and RNA binding proteins which undergo assembly in response to stress-induced inactivation of translation initiation. In general, SG recruitment is limited to a subpopulation of a given mRNA species and RNA-seq analyses of purified SGs revealed that signal sequence-encoding (i.e. endoplasmic reticulum (ER)-targeted) transcripts are significantly under-represented, consistent with prior reports that ER localization can protect mRNAs from SG recruitment. Using translational profiling, cell fractionation, and single molecule mRNA imaging, we examined SG biogenesis following activation of the unfolded protein response (UPR) by 1,4-dithiothreitol (DTT) and report that gene-specific subsets of cytosolic and ER-targeted mRNAs can be recruited into SGs. Furthermore, we demonstrate that SGs form in close proximity to or directly associated with the ER membrane. ER-associated SG assembly was also observed during arsenite stress, suggesting broad roles for the ER in SG biogenesis. Recruitment of a given mRNA into SGs required stress-induced translational repression, though translational inhibition was not solely predictive of an mRNA's propensity for SG recruitment. SG formation was prevented by the transcriptional inhibitors actinomycin D or triptolide, suggesting a functional link between gene transcriptional state and SG biogenesis. Collectively these data demonstrate that ER-targeted and cytosolic mRNAs can be recruited into ER-associated SGs and this recruitment is sensitive to transcriptional inhibition. We propose that newly transcribed mRNAs exported under conditions of suppressed translation initiation are primary SG substrates, with the ER serving as the central subcellular site of SG formation.
    Keywords:  endoplasmic reticulum; mRNA; stress granule; translational regulation; unfolded protein response
    DOI:  https://doi.org/10.1261/rna.078858.121
  3. Mol Cell Biochem. 2021 Jul 14.
    Unfolded protein response during cardiovascular disorders: a tilt towards pro-survival and cellular homeostasis.
    Shreya Das, Arunima Mondal, Jayeeta Samanta, Santanu Chakraborty, Arunima Sengupta.
      The endoplasmic reticulum (ER) is an organelle that orchestrates the production and proper assembly of an extensive types of secretory and membrane proteins. Endoplasmic reticulum stress is conventionally related to prolonged disruption in the protein folding machinery resulting in the accumulation of unfolded proteins in the ER. This disruption is often manifested due to oxidative stress, Ca2+ leakage, iron imbalance, disease conditions which in turn hampers the cellular homeostasis and induces cellular apoptosis. A mild ER stress is often reverted back to normal. However, cells retaliate to acute ER stress by activating the unfolded protein response (UPR) which comprises three signaling pathways, Activating transcription factor 6 (ATF6), inositol requiring enzyme 1 alpha (IRE1α), and protein kinase RNA-activated-like ER kinase (PERK). The UPR response participates in both protective and pro-apoptotic responses and not much is known about the mechanistic aspects of the switch from pro-survival to pro-apoptosis. When ER stress outpaces UPR response then cell apoptosis prevails which often leads to the development of various diseases including cardiomyopathies. Therefore, it is important to identify molecules that modulate the UPR that may serve as promising tools towards effective treatment of cardiovascular diseases. In this review, we elucidated the latest advances in construing the contribution imparted by the three arms of UPR to combat the adverse environment in the ER to restore cellular homeostasis during cardiomyopathies. We also summarized the various therapeutic agents that plays crucial role in tilting the UPR response towards pro-survival.
    Keywords:  Cardioprotective; Cardiovascular diseases; Chemical; ER stress; Natural products; Unfolded protein response
    DOI:  https://doi.org/10.1007/s11010-021-04223-0
  4. PLoS Biol. 2021 Jul;19(7): e3001302
    Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans.
    Maria Sladowska, Michał Turek, Min-Ji Kim, Krzysztof Drabikowski, Ben Hur Marins Mussulini, Karthik Mohanraj, Remigiusz A Serwa, Ulrike Topf, Agnieszka Chacinska.
      Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the "mitochondrial unfolded protein response" [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the "unfolded protein response activated by mistargeting of proteins" [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity.
    DOI:  https://doi.org/10.1371/journal.pbio.3001302
  5. J Proteome Res. 2021 Jul 16.
    Integration of Metabolomics and Transcriptomics Reveals Ketone Body and Lipid Metabolism Disturbance Related to ER Stress in the Liver.
    Peng Ma, Zijing Wang, Yisa Wang, Biyu Hou, Jialin Sun, He Tian, Bowen Li, Guanghou Shui, Xiuying Yang, Xinyu Yang, Guifen Qiang, Chong Wee Liew, Guanhua Du.
      Once protein synthesis is excessive or misfolded protein becomes aggregated, which eventually overwhelms the capacity of the endoplasmic reticulum (ER), a state named ER stress would be reached. ER stress could affect many tissues, especially the liver, in which nonalcoholic fatty liver disease, liver steatosis, etc. have been reported relative. However, there is still a lack of systematic insight into ER stress in the liver, which can be obtained by integrating metabolomics and transcriptomics of the tissue. Here, tunicamycin was utilized to induce ER stress in C57BL/6N mice. Microarray and untargeted metabolomics were performed to identify the genes and metabolites significantly altered in liver tissues. Surprisingly, apart from the predictable unfolded protein response, liver lipid, arginine, and proline metabolisms were affirmed to be related to ER stress. Also, the ketone body metabolism changed most prominently in response to ER stress, with few studies backing. What is more, succinate receptor 1 (Sucnr1) may be a novel marker and therapeutical target of liver ER stress. In this study, the combination of the metabolome and transcriptome provided reliable information about liver pathological processes, including key relative pathways, potential markers, and targets involved in ER stress of the liver.
    Keywords:  ER stress; endoplasmic reticulum; liver; metabolome; transcriptome
    DOI:  https://doi.org/10.1021/acs.jproteome.1c00167
  6. Dev Biol. 2021 Jul 12. pii: S0012-1606(21)00171-8. [Epub ahead of print]
    The role of Ire1 in Drosophila eye pigmentation revealed by an RNase dead allele.
    Sahana Mitra, Hyung Don Ryoo.
      Ire1 is an endoplasmic reticulum (ER) transmembrane RNase that cleaves substrate mRNAs to help cells adapt to ER stress. Because there are cell types with physiological ER stress, loss of Ire1 results in metabolic and developmental defects in diverse organisms. In Drosophila, Ire1 mutants show developmental defects at early larval stages and in pupal eye photoreceptor differentiation. These Drosophila studies relied on a single Ire1 loss of function allele with a Piggybac insertion in the coding sequence. Here, we report that an Ire1 allele with a specific impairment in the RNase domain, H890A, unmasks previously unrecognized Ire1 phenotypes in Drosophila eye pigmentation. Specifically, we found that the adult eye pigmentation is altered, and the pigment granules are compromised in Ire1H890A homozygous mosaic eyes. Furthermore, the Ire1H890A mutant eyes had dramatically reduced Rhodopsin-1 protein levels. Drosophila eye pigment granules are most notably associated with late endosome/lysosomal defects. Our results indicate that the loss of Ire1, which would impair ER homeostasis, also results in altered adult eye pigmentation.
    Keywords:  , Pigment granules; Drosophila; Ire1; RNase; Rhodopsin-1
    DOI:  https://doi.org/10.1016/j.ydbio.2021.07.008
  7. Cell Death Dis. 2021 Jul 15. 12(7): 711
    Effect of the mitochondrial unfolded protein response on hypoxic death and mitochondrial protein aggregation.
    Junyi Yan, Chun-Ling Sun, Seokyung Shin, Marc Van Gilst, C Michael Crowder.
      Mitochondria are the main oxygen consumers in cells and as such are the primary organelle affected by hypoxia. All hypoxia pathology presumably derives from the initial mitochondrial dysfunction. An early event in hypoxic pathology in C. elegans is disruption of mitochondrial proteostasis with induction of the mitochondrial unfolded protein response (UPRmt) and mitochondrial protein aggregation. Here in C. elegans, we screen through RNAis and mutants that confer either strong resistance to hypoxic cell death or strong induction of the UPRmt to determine the relationship between hypoxic cell death, UPRmt activation, and hypoxia-induced mitochondrial protein aggregation (HIMPA). We find that resistance to hypoxic cell death invariantly mitigated HIMPA. We also find that UPRmt activation invariantly mitigated HIMPA. However, UPRmt activation was neither necessary nor sufficient for resistance to hypoxic death and vice versa. We conclude that UPRmt is not necessarily hypoxia protective against cell death but does protect from mitochondrial protein aggregation, one of the early hypoxic pathologies in C. elegans.
    DOI:  https://doi.org/10.1038/s41419-021-03979-z
  8. FEBS J. 2021 Jul 16.
    On the offense and defense: mitochondrial recovery programs amidst targeted pathogenic assault.
    Siraje A Mahmud, Mohammed A Qureshi, Mark W Pellegrino.
      Bacterial pathogens employ a variety of tactics to persist in their host and promote infection. Pathogens often target host organelles in order to benefit their survival, either through manipulation or subversion of their function. Mitochondria are regularly targeted by bacterial pathogens owing to their diverse cellular roles, including energy production and regulation of programmed cell death. However, disruption of normal mitochondrial function during infection can be detrimental to cell viability because of their essential nature. In response, cells use multiple quality control programs to mitigate mitochondrial dysfunction and promote recovery. In this review, we will provide an overview of mitochondrial recovery programs including mitochondrial dynamics, the mitochondrial unfolded protein response (UPRmt ), and mitophagy. We will then discuss the various approaches used by bacterial pathogens to target mitochondria which result in mitochondrial dysfunction. Lastly, we will discuss how cells leverage mitochondrial recovery programs beyond their role in organelle repair, to promote host defense against pathogen infection.
    Keywords:  UPRmt; defense; infection; mitochondria; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy; pathogen
    DOI:  https://doi.org/10.1111/febs.16126
  9. Cell Death Dis. 2021 Jul 14. 12(7): 701
    ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease.
    Xinpei Gao, Zhixin Jiang, Xinfeng Yan, Jiping Liu, Fengwen Li, Peng Liu, Jialu Li, Yuehua Wei, Yi Eve Sun, Yinan Zhang, Congrong Wang.
      The mitochondrial DNA m.3243A > G mutation is well-known to cause a variety of clinical phenotypes, including diabetes, deafness, and osteoporosis. Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A > G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A > G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPRmt), together with reduced Wnt/β-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPRmt, improved mitochondrial function, restored expression of GSK3B and WNT7B, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPRmt could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A > G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.
    DOI:  https://doi.org/10.1038/s41419-021-03993-1
  10. Commun Biol. 2021 Jul 16. 4(1): 884
    Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis.
    Nadya Al-Yacoub, Dilek Colak, Salma Awad Mahmoud, Maya Hammonds, Kunhi Muhammed, Olfat Al-Harazi, Abdullah M Assiri, Jehad Al-Buraiki, Waleed Al-Habeeb, Coralie Poizat.
      Endoplasmic reticulum (ER) stress induction of cell death is implicated in cardiovascular diseases. Sustained activation of ER-stress induces the unfolded protein response (UPR) pathways, which in turn activate three major effector proteins. We previously reported a missense homozygous mutation in FBXO32 (MAFbx, Atrogin-1) causing advanced heart failure by impairing autophagy. In the present study, we performed transcriptional profiling and biochemical assays, which unexpectedly revealed a reduced activation of UPR effectors in patient mutant hearts, while a strong up-regulation of the CHOP transcription factor and of its target genes are observed. Expression of mutant FBXO32 in cells is sufficient to induce CHOP-associated apoptosis, to increase the ATF2 transcription factor and to impair ATF2 ubiquitination. ATF2 protein interacts with FBXO32 in the human heart and its expression is especially high in FBXO32 mutant hearts. These findings provide a new underlying mechanism for FBXO32-mediated cardiomyopathy, implicating abnormal activation of CHOP. These results suggest alternative non-canonical pathways of CHOP activation that could be considered to develop new therapeutic targets for the treatment of FBXO32-associated DCM.
    DOI:  https://doi.org/10.1038/s42003-021-02391-9
  11. Cell Death Dis. 2021 Jul 13. 12(7): 696
    miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer.
    Jing Guo, Xuxian Zhong, Qinglin Tan, Shengnan Yang, Jiaqi Liao, Jinke Zhuge, Ziyang Hong, Qiong Deng, Qiang Zuo.
      Trastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.
    DOI:  https://doi.org/10.1038/s41419-021-03991-3
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