bims-unfpre 2022-10-30 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–10–30
six papers selected by
Susan Logue, University of Manitoba

Termination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention.
Emerging Links Between Endoplasmic Reticulum Stress Responses and Acute Kidney Injury.
DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis.
Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering.
Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors.
Dual role of IRE1α-XBP1 signaling in neurodegenerative diseases.

Nat Commun. 2022 Oct 25. 13(1): 6331

Termination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention.

Laura Matabishi-Bibi, Drice Challal, Mara Barucco, Domenico Libri, Anna Babour.

Cellular homeostasis is maintained by surveillance mechanisms that intervene at virtually every step of gene expression. In the nucleus, the yeast chromatin remodeler Isw1 holds back maturing mRNA ribonucleoparticles to prevent their untimely export, but whether this activity operates beyond quality control of mRNA biogenesis to regulate gene expression is unknown. Here, we identify the mRNA encoding the central effector of the unfolded protein response (UPR) HAC1, as an Isw1 RNA target. The direct binding of Isw1 to the 3' untranslated region of HAC1 mRNA restricts its nuclear export and is required for accurate UPR abatement. Accordingly, ISW1 inactivation sensitizes cells to endoplasmic reticulum (ER) stress while its overexpression reduces UPR induction. Our results reveal an unsuspected mechanism, in which binding of ER-stress induced Isw1 to HAC1 mRNA limits its nuclear export, providing a feedback loop that fine-tunes UPR attenuation to guarantee homeostatic adaptation to ER stress.

DOI: https://doi.org/10.1038/s41467-022-34133-8
Am J Physiol Cell Physiol. 2022 Oct 24.

Emerging Links Between Endoplasmic Reticulum Stress Responses and Acute Kidney Injury.

Aidan W Porter, Jeffrey L Brodsky, Teresa M Buck.

  All cell types must maintain homeostasis under periods of stress. To prevent the catastrophic effects of stress, all cell types also respond to stress by inducing protective pathways. Within the cell, the endoplasmic reticulum (ER) is exquisitely stress-sensitive, primarily because this organelle folds, post-translationally processes, and sorts one-third of the proteome. In the 1990s, a specialized ER stress response pathway was discovered, the unfolded protein response (UPR), which specifically protects the ER from damaged proteins and toxic chemicals. Not surprisingly, UPR-dependent responses are essential to maintain the function and viability of cells continuously exposed to stress, such as those in the kidney, which have high metabolic demands, produce myriad protein assemblies, continuously filter toxins, and synthesize ammonia. In this mini-review, we highlight recent papers that link ER stress and the UPR with acute kidney injury (AKI), a disease that arises in ~10% of all hospitalized individuals and nearly half of all people admitted to intensive care units. We conclude with a discussion of prospects for treating AKI with emerging drugs that improve ER function.

Keywords:  Chemical chaperone; Molecular chaperone; Renal physiology; Unfolded Protein Response (UPR); proteostasis

DOI:  https://doi.org/10.1152/ajpcell.00370.2022
Apoptosis. 2022 Oct 23.

DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis.

Jagoda Adamczyk-Grochala, Dominika Bloniarz, Klaudia Zielinska, Anna Lewinska, Maciej Wnuk.

  The acidic, hypoxic and nutrient-deprived tumor microenvironment may induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may exert an important cytoprotective role by promoting folding of newly synthesized proteins and cancer cell survival. The lack of DNMT2/TRDMT1 methyltransferase-mediated C38 tRNA methylation compromises translational fidelity that may result in the accumulation of misfolded and aggregated proteins leading to proteotoxic stress-related cell death. In the present study, DNMT2/TRDMT1 gene knockout-mediated effects were investigated during doxorubicin (DOX)-induced ER stress and PERK-, IRE1- and ATF6-orchestrated UPR in four genetically different cellular models of cancer (breast and cervical cancer, osteosarcoma and glioblastoma cells). Upon DOX stimulation, DNMT2/TRDMT1 gene knockout impaired PERK activation and modulated NSUN and 5-methylcytosine RNA-based responses and microRNA profiles. The lack of DNMT2/TRDMT1 gene in DOX-treated four cancer cell lines resulted in decreased levels of four microRNAs, namely, miR-23a-3p, miR-93-5p, miR-125a-5p and miR-191-5p involved in the regulation of several pathways such as ubiquitin-mediated proteolysis, amino acid degradation and translational misregulation in cancer. We conclude that DNMT2/TRDMT1 gene knockout, at least in selected cellular cancer models, affects adaptive responses associated with protein homeostasis networks that during prolonged ER stress may result in increased sensitivity to apoptotic cell death.

Keywords:  Cancer cells; DNMT2/TRDMT1; Doxorubicin; ER stress; MicroRNA expression

DOI:  https://doi.org/10.1007/s10495-022-01779-0
Int J Mol Sci. 2022 Oct 12. pii: 12130. [Epub ahead of print]23(20):

Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering.

Mark A Bieniawski, Kofi L P Stevens, Christopher M Witham, Robert F L Steuart, Vytas A Bankaitis, Carl J Mousley.

  Endoplasmic reticulum (ER) function is dedicated to multiple essential processes in eukaryotes, including the processing of secretory proteins and the biogenesis of most membrane lipids. These roles implicate a heavy burden to the organelle, and it is thus prone to fluctuations in the homeostasis of molecules which govern these processes. The unfolded protein response (UPR) is a general ER stress response tasked with maintaining the ER for optimal function, mediated by the master activator Ire1. Ire1 is an ER transmembrane protein that initiates the UPR, forming characteristic oligomers in response to irregularities in luminal protein folding and in the membrane lipid environment. The role of lipids in regulating the UPR remains relatively obscure; however, recent research has revealed a potent role for sphingolipids in its activity. Here, we identify a major role for the oxysterol-binding protein Kes1, whose activity is of consequence to the sphingolipid profile in cells resulting in an inhibition of UPR activity. Using an mCherry-tagged derivative of Ire1, we observe that this occurs due to inhibition of Ire1 to form oligomers. Furthermore, we identify that a sphingolipid presence is required for Ire1 activity, and that specific sphingolipid profiles are of major consequence to Ire1 function. In addition, we highlight cases where Ire1 oligomerization is absent despite an active UPR, revealing a potential mechanism for UPR induction where Ire1 oligomerization is not necessary. This work provides a basis for the role of sphingolipids in controlling the UPR, where their metabolism harbors a crucial role in regulating its onset.

Keywords:  Ire1; Kes1; Osh4; sphingolipids; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/ijms232012130
Pharmaceutics. 2022 Oct 19. pii: 2233. [Epub ahead of print]14(10):

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors.

Michael E Stokes, Matthew D Surman, Veronica Calvo, David Surguladze, An-Hu Li, Jennifer Gasparek, Matthew Betzenhauser, Guangyu Zhu, Hongwen Du, Alan C Rigby, Mark J Mulvihill.

  The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.

Keywords:  ER stress; PERK; UPR; cancer; diabetes; inhibitor; kinase; small molecule; structure–activity-relationship (SAR)

DOI:  https://doi.org/10.3390/pharmaceutics14102233
Neuroscience. 2022 Oct 21. pii: S0306-4522(22)00524-3. [Epub ahead of print]

Dual role of IRE1α-XBP1 signaling in neurodegenerative diseases.

Cailin Wang, Yanmin Chang, Jiahui Zhu, Rong Ma, Gang Li.

  The prevalence of neurodegenerative disease has increased as an outcome of the aging population, and effective clinical treatments for such diseases are lacking. Endoplasmic reticulum dysfunction has been identified as a causative factor in various neurological disorders. The inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) signaling pathway is the most conserved branch of the unfolded protein response, functioning in both physiological and pathological processes. The modulation of IRE1α-XBP1 signaling via genetic manipulation or drug administration has opposite effects in multiple disease models of neurodegeneration, indicating the complex and heterogeneous role of IRE1α-XBP1 signaling among neurodegenerative diseases and even at different stages within the same disease. Herein, we focus on the multifaceted nature of IRE1α-XBP1 signaling and provide a detailed overview of the latest findings regarding its biological relevance in brain physiology and neurodegenerative disease pathobiology. Moreover, the possible pharmacological targets in the IRE1α-XBP1 axis are discussed.

Keywords:  IRE1α; XBP1; autophagy; calcium; neurodegeneration; neuroinflammation; unfolded protein response

DOI:  https://doi.org/10.1016/j.neuroscience.2022.10.014