bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2022‒02‒20
five papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

  1. JCI Insight. 2022 Feb 15. pii: e157203. [Epub ahead of print]
      Kawasaki disease (KD) is the leading cause of non-congenital heart disease in children. Studies in mice and humans propound the NLRP3-IL-1β pathway as the principal driver of KD pathophysiology. Endoplasmic reticulum (ER) stress can activate the NLRP3 inflammasome, but the potential implication of ER stress in KD pathophysiology has not been investigated. We used human patient data and the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to characterize the impact of ER stress on the development of cardiovascular lesions. KD patient transcriptomics and single-cell RNA sequencing of the abdominal aorta from LCWE-injected mice revealed changes in the expression of ER stress genes. Alleviating ER stress genetically, by conditional deletion of Inositol Requiring Enzyme-1 (IRE1) in myeloid cells, or pharmacologically, by inhibition of IRE1 endoribonuclease (RNase) activity, led to significant reduction of LCWE-induced cardiovascular lesion formation as well as reduced caspase-1 activity and IL-1β secretion. These results demonstrate the causal relationship of ER stress to KD pathogenesis, and highlight IRE1 RNase activity as a potential new therapeutic target.
    Keywords:  Cell stress; Immunology; Mouse models; Vascular Biology; Vasculitis
  2. Aging Cell. 2022 Feb 16. e13558
      Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER ) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a flux "signature" of the UPRER in vivo in mouse liver was developed by inducing ER stress with tunicamycin and measuring rates of both proteome-wide translation and de novo lipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared with young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice. De novo lipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, a significant reduction was seen only in the triglyceride fraction. These data indicate that aged mice have an exaggerated metabolic flux response to ER stress, which may indicate that aging renders the UPRER less effective in resolving proteotoxic stress.
    Keywords:  aging; de novo lipogenesis; endoplasmic reticulum; proteome dynamics; proteomics; unfolded protein response
  3. Am J Physiol Lung Cell Mol Physiol. 2022 Feb 16.
      After lung injury, "damage-associated transient progenitors" (DATPs) emerge, representing a transitional state between injured epithelial cells and newly regenerated alveoli. DATPs express profibrotic genes, suggesting that they might promote idiopathic pulmonary fibrosis (IPF). However, the molecular pathways that induce and/or maintain DATPs are incompletely understood. Here we show that the bifunctional kinase/RNase-IRE1α-a central mediator of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress is a critical promoter of DATP abundance and function. Administration of a nanomolar-potent, mono-selective kinase inhibitor of IRE1α (KIRA8)-or conditional epithelial IRE1α gene knockout-both reduce DATP cell number and fibrosis in the bleomycin model, indicating that IRE1α cell-autonomously promotes transition into the DATP state. IRE1α enhances the profibrotic phenotype of DATPs, since KIRA8 decreases expression of integrin αvβ6, a key activator of TGFβ in pulmonary fibrosis, corresponding to decreased TGFβ-induced gene expression in the epithelium and decreased collagen accumulation around DATPs. Furthermore, IRE1α regulates DNA damage response (DDR) signaling, previously shown to promote the DATP phenotype, as IRE1α loss-of-function decreases H2AX phosphorylation, Cdkn1a (p21) expression, and DDR-associated secretory gene expression. Finally, KIRA8 treatment increases the differentiation of Krt19CreERT2-lineage-traced DATPs into type 1 alveolar epithelial cells after bleomycin injury, indicating that relief from IRE1α signaling enables DATPs to exit the transitional state. Thus, IRE1α coordinates a network of stress pathways that conspire to entrap injured cells in the DATP state. Pharmacologic blockade of IRE1α signaling helps resolve the DATP state, thereby ameliorating fibrosis and promoting salutary lung regeneration.
    Keywords:  ER stress; Fibrosis; Lung Progenitor Cells; Lung Regeneration; Unfolded Protein Response
  4. PLoS Biol. 2022 Feb 18. 20(2): e3001569
      The sequence space accessible to evolving proteins can be enhanced by cellular chaperones that assist biophysically defective clients in navigating complex folding landscapes. It is also possible, at least in theory, for proteostasis mechanisms that promote strict quality control to greatly constrain accessible protein sequence space. Unfortunately, most efforts to understand how proteostasis mechanisms influence evolution rely on artificial inhibition or genetic knockdown of specific chaperones. The few experiments that perturb quality control pathways also generally modulate the levels of only individual quality control factors. Here, we use chemical genetic strategies to tune proteostasis networks via natural stress response pathways that regulate the levels of entire suites of chaperones and quality control mechanisms. Specifically, we upregulate the unfolded protein response (UPR) to test the hypothesis that the host endoplasmic reticulum (ER) proteostasis network shapes the sequence space accessible to human immunodeficiency virus-1 (HIV-1) envelope (Env) protein. Elucidating factors that enhance or constrain Env sequence space is critical because Env evolves extremely rapidly, yielding HIV strains with antibody- and drug-escape mutations. We find that UPR-mediated upregulation of ER proteostasis factors, particularly those controlled by the IRE1-XBP1s UPR arm, globally reduces Env mutational tolerance. Conserved, functionally important Env regions exhibit the largest decreases in mutational tolerance upon XBP1s induction. Our data indicate that this phenomenon likely reflects strict quality control endowed by XBP1s-mediated remodeling of the ER proteostasis environment. Intriguingly, and in contrast, specific regions of Env, including regions targeted by broadly neutralizing antibodies, display enhanced mutational tolerance when XBP1s is induced, hinting at a role for host proteostasis network hijacking in potentiating antibody escape. These observations reveal a key function for proteostasis networks in decreasing instead of expanding the sequence space accessible to client proteins, while also demonstrating that the host ER proteostasis network profoundly shapes the mutational tolerance of Env in ways that could have important consequences for HIV adaptation.
  5. Antioxid Redox Signal. 2022 Feb 15.
      AIMS: The skeletal muscle maintains glucose disposal via insulin signaling and glucose transport. The progression of diabetes and insulin resistance is critically influenced by endoplasmic reticulum (ER) stress. D-allulose, a low-calorie sugar substitute, has shown crucial physiological activities under conditions involving hyperglycemia and insulin resistance. However, the molecular mechanisms of D-allulose in the progression of diabetes have not been fully elucidated. Here, we evaluated the effect of D-allulose on hyperglycemia-associated ER stress responses in human skeletal myoblasts and db/db diabetic and high-fat-diet (HFD)-fed mice.RESULTS: D-allulose effectively controlled glycemic markers such as insulin and HbA1C, showing anti-diabetic effects by inhibiting the disruption of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and glucose transporter 4 (GLUT4) expression, in which the PI3K/Akt pathway is involved. The levels of glucose dysmetabolism-based NADPH oxidase, such as Nox4, were highly increased, and their interaction with IRE1α and the resultant sulfonation-RIDD-SIRT1 decay were also highly increased under diabetic conditions, which were controlled with D-allulose treatment. Skeletal muscle cells grown with a high glucose medium supplemented with D-allulose showed controlled IRE1α sulfonation-RIDD-SIRT1 decay, in which Nox4 was involved. Innovation and Conclusion: The study observations indicate that D-allulose contributes to the muscular glucose disposal in the diabetic state where ER-localized Nox4-induced IRE1α sulfonation results in the decay of SIRT1, a core factor for controlling glucose metabolism.