bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021–06–27
seven papers selected by
Matías Eduardo González Quiroz, Worker’s Hospital
  1. Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy.
  2. The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson's Disease.
  3. S-acylation of Orai1 regulates store-operated Ca2+ entry.
  4. Hepatic X-box binding protein 1 and unfolded protein response is impaired in weanling mice with resultant hepatic injury.
  5. The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity.
  6. Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.
  7. Better brain training for treating psychological conditions.
  1. Lab Invest. 2021 Jun 25.
    Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy.
    Hung-Wei Kan, Chin-Hong Chang, Ying-Shuang Chang, Yi-Ting Ko, Yu-Lin Hsieh.
      We investigated the mediating roles of activating transcription factor 3 (ATF3), an injury marker, or C-type lectin member 5A (CLEC5A), an inflammatory response molecule, in the induction of endoplasmic reticulum (ER) stress and neuroinflammation in diabetic peripheral neuropathy in ATF3 and CLEC5A genetic knockout (aft3-/- and clec5a-/-, respectively) mice. ATF3 was expressed intranuclearly and was upregulated in mice with diabetic peripheral neuropathy (DN) and clec5a-/- mice. The DN and clec5a-/- groups also exhibited neuropathic behavior, but not in the aft3-/- group. The upregulation profiles of cytoplasmic polyadenylation element-binding protein, a protein translation-regulating molecule, and the ER stress-related molecules of inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α in the DN and clec5a-/- groups were correlated with neuropathic behavior. Ultrastructural evidence confirmed ER stress induction and neuroinflammation, including microglial enlargement and proinflammatory cytokine release, in the DN and clec5a-/- mice. By contrast, the induction of ER stress and neuroinflammation did not occur in the aft3-/- mice. Furthermore, the mRNA of reactive oxygen species-removing enzymes such as superoxide dismutase, heme oxygenase-1, and catalase were downregulated in the DN and clec5a-/- groups but were not changed in the aft3-/- group. Taken together, the results indicate that intraneuronal ATF3, but not CLEC5A, mediates the induction of ER stress and neuroinflammation associated with diabetic neuropathy.
    DOI:  https://doi.org/10.1038/s41374-021-00630-5
  2. Front Aging Neurosci. 2021 ;13 691881
    The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson's Disease.
    Haigang Ren, Wanqing Zhai, Xiaojun Lu, Guanghui Wang.
      Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment. However, although ER stress/UPR and autophagy appear to be independent cellular processes, they are closely related to each other. In this review, we focused on the roles and molecular cross-links between ER stress/UPR and autophagy in PD pathology. We systematically reviewed and summarized the most recent advances in regulation of ER stress/UPR and autophagy, and their cross-linking mechanisms. We also reviewed and discussed the mechanisms of the coexisting ER stress/UPR activation and dysregulated autophagy in the lesion regions of PD patients, and the underlying roles and molecular crosslinks between ER stress/UPR activation and the dysregulated autophagy in DA neurodegeneration induced by PD-associated genetic factors and PD-related neurotoxins. Finally, we indicate that the combined regulation of ER stress/UPR and autophagy would be a more effective treatment for PD rather than regulating one of these conditions alone.
    Keywords:  ER stress; Parkinson’s disease; UPR; autophagy; cross-link; α-synuclein
    DOI:  https://doi.org/10.3389/fnagi.2021.691881
  3. J Cell Sci. 2022 03 01. pii: jcs258579. [Epub ahead of print]135(5):
    S-acylation of Orai1 regulates store-operated Ca2+ entry.
    Savannah J West, Goutham Kodakandla, Qioachu Wang, Ritika Tewari, Michael X Zhu, Darren Boehning, Askar M Akimzhanov.
      Store-operated Ca2+ entry is a central component of intracellular Ca2+ signaling pathways. The Ca2+ release-activated channel (CRAC) mediates store-operated Ca2+ entry in many different cell types. The CRAC channel is composed of the plasma membrane (PM)-localized Orai1 channel and endoplasmic reticulum (ER)-localized STIM1 Ca2+ sensor. Upon ER Ca2+ store depletion, Orai1 and STIM1 form complexes at ER-PM junctions, leading to the formation of activated CRAC channels. Although the importance of CRAC channels is well described, the underlying mechanisms that regulate the recruitment of Orai1 to ER-PM junctions are not fully understood. Here, we describe the rapid and transient S-acylation of Orai1. Using biochemical approaches, we show that Orai1 is rapidly S-acylated at cysteine 143 upon ER Ca2+ store depletion. Importantly, S-acylation of cysteine 143 is required for Orai1-mediated Ca2+ entry and recruitment to STIM1 puncta. We conclude that store depletion-induced S-acylation of Orai1 is necessary for recruitment to ER-PM junctions, subsequent binding to STIM1 and channel activation.
    Keywords:  Ca2+ channel; Calcium; Orai1; Palmitoylation; S-acylation
    DOI:  https://doi.org/10.1242/jcs.258579
  4. Hepatology. 2021 Jun 25.
    Hepatic X-box binding protein 1 and unfolded protein response is impaired in weanling mice with resultant hepatic injury.
    Alyssa Kriegermeier, Angela Hyon, Meredith Sommars, Susan Hubchak, Brian LeCuyer, Xiaoying Liu, Grant Barish, Richard M Green.
       BACKGROUND & AIMS: The unfolded protein response (UPR) is a coordinated cellular response to endoplasmic reticulum (ER) stress that functions to maintain cellular homeostasis. When ER stress is unresolved, the UPR can trigger apoptosis. Pathways within the UPR influence bile acid metabolism in adult animal models and adult human liver diseases, however the UPR has not been studied in young animal models or pediatric liver diseases. In this study we sought to determine if weanling age mice had altered UPR activation compared to adult mice which could lead to increased bile acid induced hepatic injury APPROACH & RESULTS: We demonstrate that after 7 days of cholic acid (CA) feeding to wild type (WT) animals, weanling age mice have a 2-fold greater serum ALT levels compared to adult mice, with increased hepatic apoptosis. Weanling mice fed CA have increased hepatic nuclear X-box binding protein 1 spliced (XBP1s) expression, but cannot increase expression of its protective downstream targets endoplasmic reticulum DNA J domain-containing protein 4 (ERdj4) and ER degradation enhancing α-mannoside (EDEM). In response to tunicamycin induced ER stress, young mice have blunted expression of several UPR pathways compared to adult mice. CA feeding to adult liver-specific XBP1 knockout (LS-XBP1-/- ) mice, which are unable to resolve hepatic ER stress, leads to increased serum ALT and C/EBP homologous protein (CHOP), a proapoptotic UPR molecule, expression to levels similar to CA fed LS-XBP1-/- weanlings.
    CONCLUSIONS: Weanling mice have attenuated hepatic XBP1 signaling and impaired UPR activation with resultant increased susceptibility to bile acid induced injury.
    Keywords:  ER stress; bile acid; cholestasis; endoplasmic reticulum; liver
    DOI:  https://doi.org/10.1002/hep.32031
  5. Sci Rep. 2021 Jun 22. 11(1): 13086
    The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity.
    Dinh Thi Nguyen, Thuong Manh Le, Tsuyoshi Hattori, Mika Takarada-Iemata, Hiroshi Ishii, Jureepon Roboon, Takashi Tamatani, Takayuki Kannon, Kazuyoshi Hosomichi, Atsushi Tajima, Shusuke Taniuchi, Masato Miyake, Seiichi Oyadomari, Takashi Tanaka, Nobuo Kato, Shunsuke Saito, Kazutoshi Mori, Osamu Hori.
      While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b-/- mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b-/- neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b-/- and Calr+/- mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis.
    DOI:  https://doi.org/10.1038/s41598-021-92529-w
  6. Nat Rev Endocrinol. 2021 Jun 23.
    Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.
    Jing Yong, James D Johnson, Peter Arvan, Jaeseok Han, Randal J Kaufman.
      Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or failure to compensate for insulin resistance (type 2 diabetes mellitus; T2DM). In addition, mutations of critical genes cause monogenic diabetes. The endoplasmic reticulum (ER) is the primary site for proinsulin folding; therefore, ER proteostasis is crucial for both β-cell function and survival under physiological and pathophysiological challenges. Importantly, the ER is also the major intracellular Ca2+ storage organelle, generating Ca2+ signals that contribute to insulin secretion. ER stress is associated with the pathogenesis of diabetes mellitus. In this Review, we summarize the mutations in monogenic diabetes that play causal roles in promoting ER stress in β-cells. Furthermore, we discuss the possible mechanisms responsible for ER proteostasis imbalance with a focus on T2DM, in which both genetics and environment are considered important in promoting ER stress in β-cells. We also suggest that controlled insulin secretion from β-cells might reduce the progression of a key aspect of the metabolic syndrome, namely nonalcoholic fatty liver disease. Finally, we evaluate potential therapeutic approaches to treat T2DM, including the optimization and protection of functional β-cell mass in individuals with T2DM.
    DOI:  https://doi.org/10.1038/s41574-021-00510-4
  7. Nature. 2021 Jun 24.
    Better brain training for treating psychological conditions.
    Jyoti Madhusoodanan.
      
    Keywords:  Brain; Machine learning; Neuroscience; Psychology
    DOI:  https://doi.org/10.1038/d41586-021-01664-x
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