bims-unfpre 2024-03-24 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–03–24
ten papers selected by
Susan Logue, University of Manitoba

Exploring the IRE1 interactome: from canonical signaling functions to unexpected roles.
Dynamics of ER stress-induced gene regulation in plants.
Cell non-autonomous control of autophagy and metabolism by glial cells.
Ethnic variation and structure-function analysis of tauopathy-associated PERK alleles.
Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer.
ER stress and ERO1: Potential therapeutic targets for inherited myopathies.
Endoplasmic reticulum stress drives macrophages to produce IL-33 to favor Th2 polarization in the airways.
Gα12 and endoplasmic reticulum stress-mediated pyroptosis in a single cycle of dextran sulfate-induced mouse colitis.
DR5 disulfide bonding as a sensor and effector of protein folding stress.
Biology of Stress Responses in Aging.

J Biol Chem. 2024 Mar 15. pii: S0021-9258(24)01664-8. [Epub ahead of print] 107169

Exploring the IRE1 interactome: from canonical signaling functions to unexpected roles.

Simon Le Goupil, Hadrien Laprade, Marc Aubry, Eric Chevet.

  The unfolded protein response (UPR) is a mechanism aiming at restoring endoplasmic reticulum (ER) homeostasis and is likely involved in other adaptive pathways. The UPR is transduced by three proteins acting as sensors and triggering downstream signaling pathways. Among them, IRE1α (referred to as IRE1 hereafter), an ER-resident type I transmembrane protein, exerts its function through both kinase and endoribonuclease activities, resulting in both XBP1 mRNA splicing and RNA degradation (Regulated IRE1 Dependent Decay, RIDD). An increasing number of studies have reported protein-protein interactions (PPi) as regulators of these signaling mechanisms, and additionally, driving other non-canonical functions. In this review, we deliver evolutive and structural insights on IRE1 and further describe how this protein interaction network (interactome) regulates IRE1 signaling abilities or mediates other cellular processes through catalytic-independent mechanisms. Moreover, we focus on newly discovered targets of IRE1 kinase activity and discuss potentially novel IRE1 functions based on the nature of the interactome, thereby identifying new fields to explore regarding this protein's biological roles.

Keywords:  Endoplasmic reticulum; IRE1; Unfolded Protein Response; interactome; protein homeostasis; signaling; stress

DOI:  https://doi.org/10.1016/j.jbc.2024.107169
Nat Rev Genet. 2024 Mar 18.

Dynamics of ER stress-induced gene regulation in plants.

Dae Kwan Ko, Federica Brandizzi.

Endoplasmic reticulum (ER) stress is a potentially lethal condition that is induced by the abnormal accumulation of unfolded or misfolded secretory proteins in the ER. In eukaryotes, ER stress is managed by the unfolded protein response (UPR) through a tightly regulated, yet highly dynamic, reprogramming of gene transcription. Although the core principles of the UPR are similar across eukaryotes, unique features of the plant UPR reflect the adaptability of plants to their ever-changing environments and the need to balance the demands of growth and development with the response to environmental stressors. The past decades have seen notable progress in understanding the mechanisms underlying ER stress sensing and signalling transduction pathways, implicating the UPR in the effects of physiological and induced ER stress on plant growth and crop yield. Facilitated by sequencing technologies and advances in genetic and genomic resources, recent efforts have driven the discovery of transcriptional regulators and elucidated the mechanisms that mediate the dynamic and precise gene regulation in response to ER stress at the systems level.

DOI: https://doi.org/10.1038/s41576-024-00710-4
iScience. 2024 Apr 19. 27(4): 109354

Cell non-autonomous control of autophagy and metabolism by glial cells.

Melissa G Metcalf, Samira Monshietehadi, Arushi Sahay, Jenni Durieux, Ashley E Frakes, Martina Velichkovska, Cesar Mena, Amelia Farinas, Melissa Sanchez, Andrew Dillin.

  Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, and longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.

Keywords:  Biological sciences; Cell biology; Functional aspects of cell biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2024.109354
medRxiv. 2024 Mar 04. pii: 2024.03.03.24303689. [Epub ahead of print]

Ethnic variation and structure-function analysis of tauopathy-associated PERK alleles.

Goonho Park, Angela Galdamez, Keon-Hyoung Song, Masako Le, Kyle Kim, Jonathan H Lin.

EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages. We assembled a comprehensive data set of human PERK variants associated with Wolcott Rallison Syndrome (WRS), tauopathies, and bioinformatically predicted loss-of-function, referencing the gnomAD, Ensembl, and NCBI databases. We found extensive racial/ethnic variation in the prevalence of common PERK polymorphisms linked to tauopathies. Using SWISS-MODEL, we identified structural perturbations in the ER stress-sensing luminal domain dimers/oligomers of tauopathy-associated PERK variants, Haplotypes A and B, in combination with another tauopathy-linked R240H mutation. Recombinant expression of disease-associated variants in vitro revealed altered PERK signal transduction kinetics in response to ER stress compared to the predominant non-disease variant. In summary, our data further substantiates that human PERK variants identified in tauopathy genetic studies negatively impact PERK structure, function, and downstream signaling with significant variations in prevalence among different racial and ethnic groups.

DOI: https://doi.org/10.1101/2024.03.03.24303689
Mol Med. 2024 Mar 20. 30(1): 40

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer.

Siqi Yuan, Dan She, Shangming Jiang, Nan Deng, Jiayi Peng, Ling Ma.

  The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways-inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER's protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions.

Keywords:  Cancer; Endoplasmic reticulum stress; Metabolic; Neurodegenerative diseases; Signaling pathway; Therapeutic strategies

DOI:  https://doi.org/10.1186/s10020-024-00808-9
Cell Rep Med. 2024 Mar 19. pii: S2666-3791(24)00106-X. [Epub ahead of print]5(3): 101462

ER stress and ERO1: Potential therapeutic targets for inherited myopathies.

Anirban Roy, Aniket S Joshi, Ashok Kumar.

Selenoprotein N-related myopathy (SEPN1-RM) is a genetic disease that causes muscle weakness and respiratory failure. Germani et al.1 demonstrate that diaphragm weakness in SEPN1-RM is prevented by the inhibition of ER stress or ERO1 oxidoreductase regulated by transcription factor CHOP.

DOI: https://doi.org/10.1016/j.xcrm.2024.101462
J Leukoc Biol. 2024 Mar 22. pii: qiad109. [Epub ahead of print]

Endoplasmic reticulum stress drives macrophages to produce IL-33 to favor Th2 polarization in the airways.

Yuan Xiao, Huangping Zhang, Yu Liu, Lihua Mo, Yun Liao, Qinmiao Huang, Liteng Yang, Caijie Zhou, Jiangqi Liu, Xizhuo Sun, Haiqiong Yu, Pingchang Yang.

  Interleukin (IL)-33 is a key driver of T helper 2 (Th2) cell polarization. Endoplasmic reticulum (ER) stress plays a role in the skewed T cell activation. The objective of this project is to elucidate the role of IL-33 derived from macrophages in inducing Th2 polarization in the airways. In this study, bronchoalveolar lavage fluids (BALF) were collected from patients with asthma and healthy control subjects. Macrophages were isolated from the BALF by flow cytometry cell sorting. An asthmatic mouse model was established using the ovalbumin/alum protocol. The results showed that increased IL33 gene activity and ER stress-related molecules in BALF-derived M2a macrophages was observed in asthmatic patients. Levels of IL33 gene activity in M2a cells were positively correlated with levels of asthma response in asthma patients. Sensitization exacerbated the ER stress in the airway macrophages, which increased the expression of IL-33 in macrophages of airway in sensitized mice. Conditional ablation of Il33 or Perk or Atf4 genes in macrophages prevented induction of airway allergy in mice. In conclusion, asthma airway macrophages express high levels of IL-33 and at high ER stress status. Inhibition of IL-33 or ER stress in macrophages can effectively alleviate experimental asthma.

Keywords:  IL-33; asthma; endoplasmic reticulum stress; immunity; macrophage

DOI:  https://doi.org/10.1093/jleuko/qiad109
Sci Rep. 2024 03 15. 14(1): 6335

Gα12 and endoplasmic reticulum stress-mediated pyroptosis in a single cycle of dextran sulfate-induced mouse colitis.

Jihoon Tak, Quanxi An, Sang Gil Lee, Chang Hoon Lee, Sang Geon Kim.

  Inflammatory bowel disease (IBD) pathogenesis involves complex inflammatory events and cell death. Although IBD involves mainly necrosis in the digestive tract, pyroptosis has also been recognized. Nonetheless, the underlying basis is elusive. Gα12/13 overexpression may affect endoplasmic reticulum (ER) stress. This study examined how Gα12/13 and ER stress affect pyroptosis using dextran sulfate sodium (DSS)-induced colitis models. Gα12/13 levels were increased in the distal and proximal colons of mice exposed to a single cycle of DSS, as accompanied by increases of IRE1α, ATF6, and p-PERK. Moreover, Il-6, Il-1β, Ym1, and Arg1 mRNA levels were increased with caspase-1 and IL-1β activation, supportive of pyroptosis. In the distal colon, RIPK1/3 levels were enhanced to a greater degree, confirming necroptosis. By contrast, the mice subjected to three cycles of DSS treatments showed decreases of Gα12/13, as accompanied by IRE1α and ATF6 suppression, but increases of RIPK1/3 and c-Cas3. AZ2 treatment, which inhibited Gα12, has an anti-pyroptotic effect against a single cycle of colitis. These results show that a single cycle of DSS-induced colitis may cause ER stress-induced pyroptosis as mediated by Gα12 overexpression in addition to necroptosis, but three cycles model induces only necroptosis, and that AZ2 may have an anti-pyroptotic effect.

Keywords:  Colitis; ER stress; Gα12/Gα13; Inflammatory bowel disease; Pyroptosis

DOI:  https://doi.org/10.1038/s41598-024-56685-z
bioRxiv. 2024 Mar 07. pii: 2024.03.04.583390. [Epub ahead of print]

DR5 disulfide bonding as a sensor and effector of protein folding stress.

Mary E Law, Zaafir M Dulloo, Samantha R Eggleston, Gregory P Takacs, Grace M Alexandrow, Mengxiong Wang, Hanyu Su, Bianca Forsyth, Chi-Wu Chiang, Abhisheak Sharma, Siva Rama Raju Kanumuri, Olga A Guryanova, Jeffrey K Harrison, Boaz Tirosh, Ronald K Castellano, Brian K Law.

New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity, but TRAIL analogs or agonistic antibodies targeting these receptors have not received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may bypass some of the pharmacological limitations of these protein drugs. Previously described Disulfide bond Disrupting Agents (DDAs) activate DR5 by altering its disulfide bonding through inhibition of the Protein Disulfide Isomerases (PDIs) ERp44, AGR2, and PDIA1. Work presented here extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of Caspase 8-Caspase 3 mediated pro-apoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy. Disulfide-defective DR5 mutants do not activate the ER stress response or stimulate autophagy, indicating that these DDA-mediated responses are separable from DR5 activation and pro-apoptotic signaling. Importantly, other ER stressors, including Thapsigargin and Tunicamycin also alter DR5 disulfide bonding in various cancer cell lines and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the Integrated Stress Response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands.

DOI: https://doi.org/10.1101/2024.03.04.583390
Aging Biol. 2023 ;pii: 20230002. [Epub ahead of print]1

Biology of Stress Responses in Aging.

Manolis Maragkakis, Sulochan Malla, Maria Hatzoglou, Aleksandra Trifunovic, Adam B Glick, Toren Finkel, Valter D Longo, Susmita Kaushik, Pura Muñoz-Cánoves, Gordon J Lithgow, Nirinjini Naidoo, Lauren N Booth, Matthew J Payea, Allison B Herman, Rafael de Cabo, David M Wilson, Luigi Ferrucci, Myriam Gorospe.

On April 28th, 2022, a group of scientific leaders gathered virtually to discuss molecular and cellular mechanisms of responses to stress. Conditions of acute, high-intensity stress are well documented to induce a series of adaptive responses that aim to promote survival until the stress has dissipated and then guide recovery. However, high-intensity or persistent stress that goes beyond the cell's compensatory capacity are countered with resilience strategies that are not completely understood. These adaptative strategies, which are an essential component of the study of aging biology, were the theme of the meeting. Specific topics discussed included mechanisms of proteostasis, such as the unfolded protein response (UPR) and the integrated stress response (ISR), as well as mitochondrial stress and lysosomal stress responses. Attention was also given to regulatory mechanisms and associated biological processes linked to age-related conditions, such as muscle loss and regeneration, cancer, senescence, sleep quality, and degenerative disease, with a general focus on the relevance of stress responses to frailty. We summarize the concepts and potential future directions that emerged from the discussion and highlight their relevance to the study of aging and age-related chronic diseases.

DOI: https://doi.org/10.59368/agingbio.20230001