bims-unfpre 2024-12-15 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–12–15
eight papers selected by
Susan Logue, University of Manitoba

TUDCA modulates drug bioavailability to regulate resistance to acute ER stress in Saccharomyces cerevisiae.
STIMulating IRE1: How store-operated Ca2+ entry intersects with ER proteostasis.
Endoplasmic reticulum stress in acute lung injury and pulmonary fibrosis.
Polysulfide and persulfide-mediated activation of the PERK-eIF2α-ATF4 pathway increases Sestrin2 expression and reduces methylglyoxal toxicity.
Loss of FIC-1-mediated AMPylation activates the UPR ER and upregulates cytosolic HSP70 chaperones to suppress polyglutamine toxicity.
Single-nucleus transcriptomic analysis reveals the regulatory circuitry of myofiber XBP1 during regenerative myogenesis.
The cGAS-STING/PERK-eIF2α: Individual or Potentially Collaborative Signaling Transduction in Cardiovascular Diseases.
Noise induces Ca2+ signaling waves and Chop/S-Xbp1 expression in the hearing cochlea.

Mol Biol Cell. 2024 Dec 11. mbcE24040147

TUDCA modulates drug bioavailability to regulate resistance to acute ER stress in Saccharomyces cerevisiae.

Sarah R Chadwick, Samuel Stack-Couture, Matthew D Berg, Sonja Di Gregorio, Bryan Lung, Julie Genereaux, Robyn D Moir, Christopher J Brandl, Ian M Willis, Erik L Snapp, Patrick Lajoie.

Cells counter accumulation of misfolded secretory proteins in the endoplasmic reticulum (ER) through activation of the Unfolded Protein Response (UPR). Small molecules termed chemical chaperones can promote protein folding to alleviate ER stress. The bile acid tauroursodeoxycholic acid (TUDCA), has been described as a chemical chaperone. While promising in models of protein folding diseases, TUDCA's mechanism of action remains unclear. Here, we found TUDCA can rescue growth of yeast treated with the ER stressor tunicamycin (Tm), even in the absence of a functional UPR. In contrast, TUDCA failed to rescue growth on other ER stressors. Nor could TUDCA attenuate chronic UPR associated with specific gene deletions or over-expression of a misfolded mutant secretory protein. Neither pretreatment with or delayed addition of TUDCA conferred protection against Tm. Importantly, attenuation of Tm-induced toxicity required TUDCA's critical micelle forming concentration, suggesting a mechanism where TUDCA directly sequesters drugs. Indeed, in several assays, TUDCA treated cells closely resembled cells treated with lower doses of Tm. In addition, we found TUDCA can inhibit dyes from labeling intracellular compartments. Thus, our study challenges the model of TUDCA as a chemical chaperone and suggests that TUDCA decreases drug bioavailability, allowing cells to adapt to ER stress.

DOI: https://doi.org/10.1091/mbc.E24-04-0147
Cell Calcium. 2024 Nov 29. pii: S0143-4160(24)00138-6. [Epub ahead of print]125 102980

STIMulating IRE1: How store-operated Ca2+ entry intersects with ER proteostasis.

Maria Livia Sassano, Robbe Van Gorp, Geert Bultynck, Patrizia Agostinis.

  The endoplasmic reticulum (ER) controls intracellular Ca2+ dynamics. Depletion of ER Ca2+ stores results in short-term activation of store-operated Ca2+ entry (SOCE) via STIM1/Orai1 at ER-plasma membrane (ER-PM) contact sites (MCSs) and the long-term activation of the unfolded protein response (UPR), securing ER proteostasis. Recent work by Carreras-Sureda and colleagues describes a bidirectional control between IRE1 and STIM1 within the ER lumen that regulates ER-PM contact assembly and SOCE to sustain T-cell activation and myoblast differentiation.

Keywords:  IP3 receptors; IRE1; STIM1; Store-operated calcium entry; Unfolded protein response

DOI:  https://doi.org/10.1016/j.ceca.2024.102980
FASEB J. 2024 Dec 15. 38(23): e70232

Endoplasmic reticulum stress in acute lung injury and pulmonary fibrosis.

Zhiheng Sun, Wanyu He, Huiwen Meng, Peizhi Li, Junxing Qu.

  Pulmonary fibrosis (PF) is a progressive and irreversible lung disease that leads to diminished lung function, respiratory failure, and ultimately death and typically has a poor prognosis, with an average survival time of 2 to 5 years. Related articles suggested that endoplasmic reticulum (ER) stress played a critical role in the occurrence and progression of PF. The ER is responsible for maintaining protein homeostasis. However, factors such as aging, hypoxia, oxidative stress, or inflammation can disrupt this balance, promoting the accumulation of misfolded proteins in the ER and triggering ER stress. To cope with this situation, cells activate the unfolded protein response (UPR). Since acute lung injury (ALI) is one of the key onset events of PF, in this review, we will discuss the role of ER stress in ALI and PF by activating multiple signaling pathways and molecular mechanisms that affect the function and behavior of different cell types, with a focus on epithelial cells, fibroblasts, and macrophages. Linking ER stress to these cell types may broaden our understanding of the mechanisms underlying lung fibrosis and help us target these cells through these mechanisms. The relationship between ER stress and PF is still evolving, and future research will explore new strategies to regulate UPR pathways, providing novel therapeutic targets.

Keywords:  acute lung injury; endoplasmic reticulum stress; epithelial cells; fibroblasts; macrophages; pulmonary fibrosis

DOI:  https://doi.org/10.1096/fj.202401849RR
Redox Biol. 2024 Dec 05. pii: S2213-2317(24)00428-2. [Epub ahead of print]79 103450

Polysulfide and persulfide-mediated activation of the PERK-eIF2α-ATF4 pathway increases Sestrin2 expression and reduces methylglyoxal toxicity.

Shin Koike, Hideo Kimura, Yuki Ogasawara.

  Unfolded protein response (UPR) is activated in cells under endoplasmic reticulum (ER) stress. One sensor protein involved in this response is PERK, which is activated through its redox-dependent oligomerization. Prolonged UPR activation is associated with the development and progression of various diseases, making it essential to understanding the redox regulation of PERK. Sulfane sulfur, such as polysulfides and persulfides, can modify the cysteine residues and regulate the function of various proteins. However, the regulatory mechanism and physiological effects of sulfane sulfur on the PERK-eIF2α-ATF4 pathway remain poorly understood. This study focuses on the persulfidation of PERK to elucidate the effects of polysulfides on the PERK-eIF2α-ATF4 pathway and investigate its cytoprotective mechanism. Here, we demonstrated that polysulfide treatment promoted the oligomerization of PERK and PTP1B in neuronal cells using western blotting under nonreducing conditions. We also observed that l-cysteine, a biological source of sulfane sulfur, promoted the oligomerization of PERK and the knockdown of CBS and 3-MST, two sulfane sulfur-producing enzymes, and reduced PERK oligomerization induced by l-cysteine treatment. Furthermore, the band shift assay and LC-MS/MS studies revealed that polysulfides and persulfides induce PTP1B and PERK persulfidation. Additionally, polysulfides promoted eIF2α phosphorylation and ATF4 accumulation in the nucleus, suggesting that polysulfides activate the PERK-eIF2α-ATF4 pathway in neuronal cells. Moreover, polysulfides protected neuronal cells from methylglyoxal-induced toxicity, and this protective effect was reduced when the expression of Sestrin2, regulated by ATF4 activity, was suppressed. This study identified a novel mechanism for the activation of the PERK-eIF2α-ATF4 pathway through persulfidation by polysulfides and persulfides. Interestingly, activation of this pathway overcame the toxicity of methylglyoxal in dependence on Sestrin2 expression. These findings deepen our understanding of neuronal diseases involving ER stress and UPR disturbance and may inspire new therapeutic strategies.

Keywords:  Methylglyoxal; Persulfide; Polysulfide; Sestrin2; UPR pathway

DOI:  https://doi.org/10.1016/j.redox.2024.103450
bioRxiv. 2024 Nov 28. pii: 2024.11.27.625751. [Epub ahead of print]

Loss of FIC-1-mediated AMPylation activates the UPR ER and upregulates cytosolic HSP70 chaperones to suppress polyglutamine toxicity.

Kate M Van Pelt, Matthias C Truttmann.

Targeted regulation of cellular proteostasis machinery represents a promising strategy for the attenuation of pathological protein aggregation. Recent work suggests that the unfolded protein response in the endoplasmic reticulum (UPR ER ) directly regulates the aggregation and toxicity of expanded polyglutamine (polyQ) proteins. However, the mechanisms underlying this phenomenon remain poorly understood. In this study, we report that perturbing ER homeostasis in Caenorhabditis elegans through the depletion of either BiP ortholog, hsp-3 or hsp-4, causes developmental arrest in worms expressing aggregation-prone polyQ proteins. This phenotype is rescued by the genetic deletion of the conserved UPR ER regulator, FIC-1. We demonstrate that the beneficial effects of fic-1 knock-out (KO) extend into adulthood, where the loss of FIC-1-mediated protein AMPylation in polyQ-expressing animals is sufficient to prevent declines in fitness and lifespan. We further show that loss of hsp-3 and hsp-4 leads to distinct, but complementary transcriptomic responses to ER stress involving all three UPR ER stress sensors (IRE-1, PEK-1, and ATF-6). We identify the cytosolic HSP70 family chaperone F44E5.4 , whose expression is increased in fic-1 -deficient animals upon ER dysregulation, as a key effector suppressing polyQ toxicity. Over-expression of F44E5.4 , but not other HSP70 family chaperones, is sufficient to rescue developmental arrest in polyQ-expressing embryos upon hsp-3 knock-down. Finally, we show that knock-down of ire-1 , pek-1 , or atf-6 blocks the upregulation of F44E5.4 in fic-1 -deficient worms. Taken together, our findings support a model in which the loss of FIC-1-mediated AMPylation engages UPR ER signaling to upregulate cytosolic chaperone activity in response to polyQ toxicity.

DOI: https://doi.org/10.1101/2024.11.27.625751
iScience. 2024 Dec 20. 27(12): 111372

Single-nucleus transcriptomic analysis reveals the regulatory circuitry of myofiber XBP1 during regenerative myogenesis.

Aniket S Joshi, Micah B Castillo, Meiricris Tomaz da Silva, Anh Tuan Vuong, Preethi H Gunaratne, Radbod Darabi, Yu Liu, Ashok Kumar.

  Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is activated in skeletal muscle under multiple conditions. However, the role of the UPR in the regulation of muscle regeneration remains less understood. We demonstrate that gene expression of various markers of the UPR is induced in both myogenic and non-myogenic cells in regenerating muscle. Genetic ablation of X-box binding protein 1 (XBP1), a downstream target of the Inositol requiring enzyme 1α (IRE1α) arm of the UPR, in myofibers attenuates muscle regeneration in adult mice. Single nucleus RNA sequencing (snRNA-seq) analysis showed that deletion of XBP1 in myofibers perturbs proteolytic systems and mitochondrial function in myogenic cells. Trajectory analysis of snRNA-seq dataset showed that XBP1 regulates the abundance of satellite cells and the formation of new myofibers in regenerating muscle. In addition, ablation of XBP1 disrupts the composition of non-myogenic cells in injured muscle microenvironment. Collectively, our study suggests that myofiber XBP1 regulates muscle regeneration through both cell-autonomous and -non-autonomous mechanisms.

Keywords:  Biochemistry; Cell biology; Genetics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.111372
Int J Biol Sci. 2024 ;20(15): 5868-5887

The cGAS-STING/PERK-eIF2α: Individual or Potentially Collaborative Signaling Transduction in Cardiovascular Diseases.

Xueqi Wan, Huan Zhang, Jinfan Tian, Libo Liu, Ziyu An, Xin Zhao, Lijun Zhang, Xueyao Yang, Changjiang Ge, Xiantao Song.

  Over the past several decades, a canonical pathway called the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) mediating type I interferon (IFN) release via TANK-binding kinase 1(TBK1) / IFN regulatory factor 3 (IRF3) pathway has been widely investigated and characterized. Unexpectedly, recent studies show that the cGAS-STING noncanonically activates the protein kinase RNA-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α), an essential branch of unfolded protein response (UPR), even before the activation of the TBK1/IRF3 signaling. Additionally, we found that the PERK could regulate the STING signaling besides being modulated by upstream cGAS-STING. However, earlier evidence solely focused on the unidirectional regulation of STING and PERK, lacking their functional crosstalk. Hence, we postulate that there is a complex relationship between the cGAS-STING and PERK-eIF2α pathways and that, through convergent downstream signaling, they may collaboratively contribute to the pathophysiology of cardiovascular diseases (CVDs) via the cGAS-STING/PERK-eIF2α signaling axis. This study provides a novel pathway for the development of CVDs and paves the foundation for potential therapeutic targets for CVDs.

Keywords:  CVDs; PERK-eIF2α; UPR; cGAS-STING; therapeutics

DOI:  https://doi.org/10.7150/ijbs.101247
JCI Insight. 2024 Dec 10. pii: e181783. [Epub ahead of print]

Noise induces Ca2+ signaling waves and Chop/S-Xbp1 expression in the hearing cochlea.

Yesai Park, Jiang Li, Noura Ismail Mohamad, Ian R Matthews, Peu Santra, Elliott H Sherr, Dylan K Chan.

  Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response, have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways have been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice. We used a genetically encoded calcium indicator mouse model in which GCaMP is expressed specifically in hair cells or supporting cells under control of Myo15Cre or Sox2Cre, respectively. We performed live calcium imaging and UPR gene expression analysis in 8-week-old mice exposed to levels of noise that cause cochlear synaptopathy (98 db SPL) or permanent hearing loss (106 dB SPL). UPR activation occurred immediately after noise exposure and was noise dose-dependent, with the pro-apoptotic pathway upregulated only after 106 dB noise exposure. Spontaneous calcium transients in hair cells and intercellular calcium waves in supporting cells, which are present in neonatal cochleae, were quiescent in mature-hearing cochleae, but re-activated upon noise exposure. 106 dB noise exposure was associated with more persistent and expansive intercellular Ca2+ signaling wave activity. These findings demonstrated a strong and dose-dependent association between noise exposure, UPR activation, and changes in calcium homeostasis in hair cells and supporting cells, suggesting that targeting these pathways may be effective to develop treatments for noise-induced hearing loss.

Keywords:  Calcium signaling; Cell stress; Otology

DOI:  https://doi.org/10.1172/jci.insight.181783