bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒08‒08
twelve papers selected by
Susan Logue
University of Manitoba

  1. Nat Cell Biol. 2021 Aug 02.
      The memory of stresses experienced by parents can be passed on to descendants as a forecast of the challenges to come. Here, we discovered that the neuronal mitochondrial perturbation-induced systemic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans can be transmitted to offspring over multiple generations. The transgenerational activation of UPRmt is mediated by maternal inheritance of elevated levels of mitochondrial DNA (mtDNA), which causes the proteostasis stress within mitochondria. Furthermore, results from intercrossing studies using wild C. elegans strains further support that maternal inheritance of higher levels of mtDNA can induce the UPRmt in descendants. The mitokine Wnt signalling pathway is required for the transmission of elevated mtDNA levels across generations, thereby conferring lifespan extension and stress resistance to offspring. Collectively, our results reveal that the nervous system can transmit stress signals across generations by increasing mtDNA in the germline, enabling descendants to better cope with anticipated challenges.
  2. J Cell Mol Med. 2021 Aug 07.
      Stress-induced apoptosis is mediated primarily through the intrinsic pathway that involves caspase-9. We previously reported that in caspase-9-deficient cells, a protein complex containing ATG5 and Fas-associated death domain (FADD) facilitated caspase-8 activation and cell death in response to endoplasmic reticulum (ER) stress. Here, we investigated whether this complex could be activated by other forms of cell stress. We show that diverse stress stimuli, including etoposide, brefeldin A and paclitaxel, as well as heat stress and gamma-irradiation, caused formation of a complex containing ATG5-ATG12, FADD and caspase-8 leading to activation of downstream caspases in caspase-9-deficient cells. We termed this complex the 'stressosome'. However, in these cells, only ER stress and heat shock led to stressosome-dependent cell death. Using in silico molecular modelling, we propose the structure of the stressosome complex, with FADD acting as an adaptor protein, interacting with pro-caspase-8 through their respective death effector domains (DEDs) and interacting with ATG5-ATG12 through its death domain (DD). This suggests that the complex could be regulated by cellular FADD-like interleukin-1β-converting enzyme-inhibitory protein (cFLIPL ), which was confirmed experimentally. This study provides strong evidence for an alternative mechanism of caspase-8 activation involving the stressosome complex.
    Keywords:  apoptosis; autophagy; caspase; cell stress; integrated stress response
  3. Cell Death Dis. 2021 Aug 05. 12(8): 770
      Rare monogenic disorders often share molecular etiologies involved in the pathogenesis of common diseases. Congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) are rare pediatric disorders with symptoms that range from mild to life threatening. A biological mechanism shared among CDG and CDDG as well as more common neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis, is endoplasmic reticulum (ER) stress. We developed isogenic human cellular models of two types of CDG and the only known CDDG to discover drugs that can alleviate ER stress. Systematic phenotyping confirmed ER stress and identified elevated autophagy among other phenotypes in each model. We screened 1049 compounds and scored their ability to correct aberrant morphology in each model using an agnostic cell-painting assay based on >300 cellular features. This primary screen identified multiple compounds able to correct morphological phenotypes. Independent validation shows they also correct cellular phenotypes and alleviate each of the ER stress markers identified in each model. Many of the active compounds are associated with microtubule dynamics, which points to new therapeutic opportunities for both rare and more common disorders presenting with ER stress, such as Alzheimer's disease and amyotrophic lateral sclerosis.
  4. Biochem Soc Trans. 2021 Aug 02. pii: BST20210496. [Epub ahead of print]
      Cancer cachexia is associated with deficient response to chemotherapy. On the other hand, the tumors of cachectic patients remarkably express more chemokines and have higher immune infiltration. For immunogenicity, a strong induction of the unfolded protein response (UPR) is necessary. UPR followed by cell surface exposure of calreticulin on the dying tumor cell is essential for its engulfment by macrophages and dendritic cells. However, some tumor cells upon endoplasmic reticulum (ER) stress can release factors that induce ER stress to other cells, in the so-called transmissible ER stress (TERS). The cells that received TERS produce more interleukin 6 (IL-6) and chemokines and acquire resistance to subsequent ER stress, nutrient deprivation, and genotoxic stress. Since ER stress enhances the release of extracellular vesicles (EVs), we suggest they can mediate TERS. It was found that ER stressed cachexia-inducing tumor cells transmit factors that trigger ER stress in other cells. Therefore, considering the role of EVs in cancer cachexia, the release of exosomes can possibly play a role in the process of blunting the immunogenicity of the cachexia-associated tumors. We propose that TERS can cause an inflammatory and immunosuppressive phenotype in cachexia-inducing tumors.
    Keywords:  ER stress; cachexia; cancer; immunology; tumor microenvironment
  5. Ageing Res Rev. 2021 Jul 31. pii: S1568-1637(21)00164-1. [Epub ahead of print]70 101417
      One evident hallmark of Alzheimer's disease (AD) is the irregular accumulation of proteins due to changes in proteostasis involving endoplasmic reticulum (ER) stress. To alleviate ER stress and reinstate proteostasis, cells undergo an integrated signaling cascade called the unfolded protein response (UPR) that reduces the number of misfolded proteins and inhibits abnormal protein accumulation. Aging is associated with changes in the expression of ER chaperones and folding enzymes, leading to the impairment of proteostasis, and accumulation of misfolded proteins. The disrupted initiation of UPR prevents the elimination of unfolded proteins, leading to ER stress. In AD, the accumulation of misfolded proteins caused by sustained cellular stress leads to neurodegeneration and neuronal death. Current research has revealed that ER stress can trigger an inflammatory response through diverse transducers of UPR. Although the involvement of a neuroinflammatory component in AD has been documented for decades, whether it is a contributing factor or part of the neurodegenerative events is so far unknown. Besides, a feedback loop occurs between neuroinflammation and ER stress, which is strongly associated with neurodegenerative processes in AD. In this review, we focus on the current research on ER stress and UPR in cellular aging and neuroinflammatory processes, leading to memory impairment and synapse dysfunction in AD.
    Keywords:  Aging; Alzheimer’s disease; ER stress; Endoplasmic reticulum; Neuroinflammation; Unfolded protein response
  6. Biology (Basel). 2021 Jul 09. pii: 640. [Epub ahead of print]10(7):
      Endoplasmic reticulum (ER) stress and actors of unfolded protein response (UPR) have emerged as key hallmarks of hepatocarcinogenesis. Numerous reports have shown that the main actors in the UPR pathways are upregulated in HCC and contribute to the different facets of tumor initiation and disease progression. Furthermore, ER-stress inducers and inhibitors have shown success in preclinical HCC models. Despite the mounting evidence of the UPR's involvement in HCC pathogenesis, it remains unclear how ER-stress components can be used safely and effectively as therapeutic targets or predictive biomarkers for HCC patients. In an effort to add a clinical context to these findings and explore the translational potential of ER-stress in HCC, we performed a systematic overview of UPR-associated proteins as predictive biomarkers in HCC by mining the Human Protein Atlas database. Aside from evaluating the prognostic value of these markers in HCC, we discussed their expression in relation to patient age, sex, ethnicity, disease stage, and tissue localization. We thereby identified 44 UPR-associated proteins as unfavorable prognostic markers in HCC. The expression of these markers was found to be higher in tumors compared to the stroma of the hepatic HCC patient tissues.
    Keywords:  endoplasmic reticulum stress; hepatocellular carcinoma; unfolded protein response
  7. Biomedicines. 2021 Jul 08. pii: 791. [Epub ahead of print]9(7):
      The spliced form of X-box binding protein 1 (XBP1s) is an active transcription factor that plays a vital role in the unfolded protein response (UPR). Under endoplasmic reticulum (ER) stress, unspliced Xbp1 mRNA is cleaved by the activated stress sensor IRE1α and converted to the mature form encoding spliced XBP1 (XBP1s). Translated XBP1s migrates to the nucleus and regulates the transcriptional programs of UPR target genes encoding ER molecular chaperones, folding enzymes, and ER-associated protein degradation (ERAD) components to decrease ER stress. Moreover, studies have shown that XBP1s regulates the transcription of diverse genes that are involved in lipid and glucose metabolism and immune responses. Therefore, XBP1s has been considered an important therapeutic target in studying various diseases, including cancer, diabetes, and autoimmune and inflammatory diseases. XBP1s is involved in several unique mechanisms to regulate the transcription of different target genes by interacting with other proteins to modulate their activity. Although recent studies discovered numerous target genes of XBP1s via genome-wide analyses, how XBP1s regulates their transcription remains unclear. This review discusses the roles of XBP1s in target genes transcriptional regulation. More in-depth knowledge of XBP1s target genes and transcriptional regulatory mechanisms in the future will help develop new therapeutic targets for each disease.
    Keywords:  ATF6; ER stress; IRE1; RIDD; UPR; XBP1s; unfolded protein response
  8. J Cell Sci. 2021 Aug 05. pii: jcs.258685. [Epub ahead of print]
      The phase separation of the non-membrane bound Sec bodies occurs in Drosophila S2 cells by coalescence of components of the ER exit sites under the stress of amino-acid starvation. Here we address which signaling pathways cause Sec body formation and find that two pathways are critical. The first is the activation of the salt inducible kinases (SIK) by Na+ stress, that when it is strong is sufficient. The second is activation of IRE1 and PERK downstream of ER stress induced by absence of amino- acids, which needs to be combined with moderate salt stress to induce Sec body formation. SIK and IRE1/PERK activation appear to potentiate each other through the stimulation of the unfolded protein response, a key parameter in Sec body formation. This work pioneers the role of SIK in phase transition and re-enforces the role of IRE1 and PERK as a metabolic sensor for the level of circulating amino-acids and salt.
    Keywords:  Amino-acid starvation; Drosophila S2 cells; Phase separation; Salt stress; Sec body; Unfolded Protein Response
  9. ACS Chem Neurosci. 2021 Aug 02.
      The IRE1/XBP1 signaling pathway is the most conserved component of the endoplasmic reticulum unfolded protein response (UPRER). Activating this branch to correct defects in ER proteostasis is regarded as a promising anti-Parkinson's disease (PD) strategy. P-53 is a marine-derived xyloketal B analog which exhibited potential neuroprotective activities in previous research studies; however, the molecular mechanism underneath its protective effect remains unknown. Herein, a transcriptomic approach was introduced to explore the protective mechanism of P-53. RNA microarray profiling was conducted based on an MPP+-induced C. elegans PD model, and bioinformatics analyses including GO enrichment and PPI network analysis were subsequently performed. In particular, the recovery of the impaired UPRER was highlighted as a main physiological change caused by P-53, and a cluster of genes including abu and hsp family genes which are involved in the IRE1/XBP1 branch of the UPRER were identified as the key genes related to its neuroprotective effect. The transcription levels of these key genes were validated by RT-qPCR assays. Further results showed that P-53 enhanced the phosphorylation of IRE1, the splicing of xbp-1 mRNA, and the translation of XBP1S and boosted the expression level of the downstream targets of the IRE1/XBP1 signaling pathway. Moreover, it was also demonstrated that P-53 accelerated the scavenging of misfolded α-synuclein and attenuated the correlative mitochondrial dysfunction. Finally, the protective effect of P-53 against MPP+-induced dopaminergic neuronal loss was assessed. Taken together, these results revealed that P-53 plays its neuroprotective role through regulating of the IRE1/XBP1 signaling pathway and laid the foundation for its further development as an ER proteostasis-regulating agent.
    Keywords:  IRE1/XBP1 signaling pathway; Parkinson’s disease (PD); Xyloketals; endoplasmic reticulum unfolded protein response (UPRER); transcriptomic profiling
  10. EMBO Rep. 2021 Aug 02. e52289
      Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation and subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, and FAM134C are essential for maintaining ER morphology in a LC3-interacting region (LIR)-dependent manner. Overexpression of any FAM134 paralogue has the capacity to significantly augment the general ER-phagy flux upon starvation or ER-stress. Global proteomic analysis of FAM134 overexpressing and knockout cell lines reveals several protein clusters that are distinctly regulated by each of the FAM134 paralogues as well as a cluster of commonly regulated ER-resident proteins. Utilizing pro-Collagen I, as a shared ER-phagy substrate, we observe that FAM134A acts in a LIR-independent manner and compensates for the loss of FAM134B and FAM134C, respectively. FAM134C instead is unable to compensate for the loss of its paralogues. Taken together, our data show that FAM134 paralogues contribute to common and unique ER-phagy pathways.
    Keywords:  Collagen; ER stress; ER-phagy; FAM134; autophagy
  11. Int J Mol Sci. 2021 Jul 29. pii: 8146. [Epub ahead of print]22(15):
      Neurodegenerative diseases are an ever-increasing problem for the rapidly aging population. Despite this, our understanding of how these neurodegenerative diseases develop and progress, is in most cases, rudimentary. Protein kinase RNA (PKR)-like ER kinase (PERK) comprises one of three unfolded protein response pathways in which cells attempt to manage cellular stress. However, because of its role in the cellular stress response and the far-reaching implications of this pathway, error within the PERK pathway has been shown to lead to a variety of pathologies. Genetic and clinical studies show a correlation between failure of the PERK pathway in neural cells and the development of neurodegeneration, but the wide array of methodology of these studies is presenting conflicting narratives about the role of PERK in these affected systems. Because of the connection between PERK and pathology, PERK has become a high value target of study for understanding neurodegenerative diseases and potentially how to treat them. Here, we present a review of the literature indexed in PubMed of the PERK pathway and some of the complexities involved in investigating the protein's role in the development of neurodegenerative diseases as well as how it may act as a target for therapeutics.
    Keywords:  PERK; endoplasmic reticulum stress; neurodegeneration; tauopathy; therapy; unfolded protein response