bims-unfpre 2024-04-28 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024‒04‒28
nine papers selected by
Susan Logue, University of Manitoba

Baseline Unfolded Protein Response Signaling Adjusts the Timing of the Mammalian Cell Cycle.
Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress.
FicD regulates adaptation to the unfolded protein response in the murine liver.
NCI 159456 PERK Inhibitor as a Targeted Therapy for Lung Cancer: An In Vitro Study.
The Zn2+ transporter ZIP7 enhances endoplasmic-reticulum-associated protein degradation and prevents neurodegeneration in Drosophila.
Irisin attenuates ventilator-induced diaphragmatic dysfunction by inhibiting endoplasmic reticulum stress through activation of AMPK.
Chemical chaperones in metabolic fitness beyond protein folding.
Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice.
PERK inhibition in zebrafish mimics human Wolcott-Rallison syndrome phenotypes.

Mol Biol Cell. 2024 Apr 24. mbcE23110419

Baseline Unfolded Protein Response Signaling Adjusts the Timing of the Mammalian Cell Cycle.

Soham P Chowdhury, Sabrina C Solley, Elena Polishchuk, Julien Bacal, Julia E Conrad, Brooke M Gardner, Diego Acosta-Alvear, Francesca Zappa.

The endoplasmic reticulum (ER) is a single-copy organelle that cannot be generated de novo, suggesting coordination between the mechanisms overseeing ER integrity and those controlling the cell cycle to maintain organelle inheritance. The Unfolded Protein Response (UPR) is a conserved signaling network that regulates ER homeostasis. Here, we show that pharmacological and genetic inhibition of the UPR sensors IRE1, ATF6, and PERK in unstressed cells delays the cell cycle, with PERK inhibition showing the most penetrant effect, which was associated with a slowdown of the G1-to-S/G2 transition. Treatment with the small molecule ISRIB to bypass the effects of PERK-dependent phosphorylation of the translation initiation factor eIF2⍺ had no such effect, suggesting that cell cycle timing depends on PERK's kinase activity but is independent of eIF2⍺ phosphorylation. Using complementary light and electron microscopy and flow cytometry-based analyses, we also demonstrate that the ER enlarges before mitosis. Together, our results suggest coordination between UPR signaling and the cell cycle to maintain ER physiology during cell division.

DOI: https://doi.org/10.1091/mbc.E23-11-0419
Int J Mol Sci. 2024 Apr 15. pii: 4368. [Epub ahead of print]25(8):

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress.

Orsolya Kapuy.

  Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by autophagy, while an excessive level of stress results in apoptosis. It has already been proven that the proper order and characteristic features of both surviving and self-killing mechanisms are controlled by negative and positive feedback loops, respectively. The new results suggest that these feedback loops are found not only within but also between branches of the UPR, fine-tuning the response to ER stress. In this review, we summarize the recent knowledge of the dynamical characteristic of endoplasmic reticulum stress response mechanism by using both theoretical and molecular biological techniques. In addition, this review pays special attention to describing the mechanism of action of the dynamical features of the feedback loops controlling cellular life-and-death decision upon ER stress. Since ER stress appears in diseases that are common worldwide, a more detailed understanding of the behaviour of the stress response is of medical importance.

Keywords:  apoptosis; autophagy; bistability; endoplasmic reticulum stress; systems biology; unfolded protein response

DOI:  https://doi.org/10.3390/ijms25084368
bioRxiv. 2024 Apr 17. pii: 2024.04.15.589620. [Epub ahead of print]

FicD regulates adaptation to the unfolded protein response in the murine liver.

Amanda K Casey, Nathan M Stewart, Naqi Zaidi, Hillery F Gray, Amelia Cox, Hazel A Fields, Kim Orth.

The unfolded protein response (UPR) is a cellular stress response that is activated when misfolded proteins accumulate in the endoplasmic reticulum (ER). The UPR elicits a signaling cascade that results in an upregulation of protein folding machinery and cell survival signals. However, prolonged UPR responses can result in elevated cellular inflammation, damage, and even cell death. Thus, regulation of the UPR response must be tuned to the needs of the cell, sensitive enough to respond to the stress but pliable enough to be stopped after the crisis has passed. Previously, we discovered that the bi-functional enzyme FicD can modulate the UPR response via post-translational modification of BiP. FicD AMPylates BiP during homeostasis and deAMPylates BiP during stress. We found this activity is important for the physiological regulation of the exocrine pancreas. Here, we explore the role of FicD in the murine liver. Like our previous studies, livers lacking FicD exhibit enhanced UPR signaling in response to short term physiologic fasting and feeding stress. However, the livers of FicD -/- did not show marked changes in UPR signaling or damage after either chronic high fat diet (HFD) feeding or acute pathological UPR induction. Intriguingly, FicD -/- mice showed changes in UPR induction and weight loss patterns following repeated pathological UPR induction. These findings show that FicD regulates UPR responses during mild physiological stress and may play a role in maintaining resiliency of tissue through adaptation to repeated ER stress.

DOI: https://doi.org/10.1101/2024.04.15.589620
Biomedicines. 2024 Apr 17. pii: 889. [Epub ahead of print]12(4):

NCI 159456 PERK Inhibitor as a Targeted Therapy for Lung Cancer: An In Vitro Study.

Wioletta Rozpędek-Kamińska, Grzegorz Galita, Natalia Siwecka, Zuzanna Granek, Julia Barczuk, Kamil Saramowicz, Ireneusz Majsterek.

  Non-small cell lung cancer (NSCLC) represents the most common histological type of lung cancer, characterized by a five-year survival rate of 15% and poor prognosis. Accumulating evidence indicates a prominent role of endoplasmic reticulum (ER) stress and the protein kinase RNA-like ER kinase (PERK)-dependent pathway of the unfolded protein response (UPR) in the pathogenesis of NSCLC. Increased expression of downstream targets of PERK was observed in various subtypes of NSCLC, and it was associated with a more aggressive phenotype, high risk of recurrence, and poor prognosis. Therefore, the present study aimed to investigate the biological effect of the selective PERK inhibitor NCI 159456 on A549 NSCLC cells and Human Pulmonary Fibroblasts (HPF) in vitro. Treatment of both normal and ER-stressed A549 cells with NCI 159456 resulted in a significant increase in the mRNA expression level of pro-apoptotic genes like activating transcription factor 4 (ATF4), DNA damage inducible transcript 3 (DDIT3), and BCL2 Associated X, Apoptosis Regulator (BAX) as well as a decreased level of the anti-apoptotic gene B-cell lymphoma 2 (Bcl-2). Cytotoxicity and genotoxicity analyses revealed that NCI 159456 significantly decreased viability and increased DNA damage in A549 cells under normal and ER stress conditions. Caspase-3 and reactive oxygen species (ROS) detection assays demonstrated that NCI 159456 significantly induced apoptosis and increased the ROS level in normal and ER-stressed A549 cells. Importantly, treatment with the inhibitor did not affect substantially normal HPF cells at any used concentration. The results indicate that PERK inhibitors could potentially be applied as a targeted therapy for NSCLC.

Keywords:  ER stress; PERK; PERK inhibitor; UPR; apoptosis; lung cancer; lung cancer treatment

DOI:  https://doi.org/10.3390/biomedicines12040889
Dev Cell. 2024 Apr 22. pii: S1534-5807(24)00228-4. [Epub ahead of print]

The Zn2+ transporter ZIP7 enhances endoplasmic-reticulum-associated protein degradation and prevents neurodegeneration in Drosophila.

Xiaoran Guo, Morgan Mutch, Alba Yurani Torres, Maddalena Nano, Nishi Rauth, Jacob Harwood, Drew McDonald, Zijing Chen, Craig Montell, Wei Dai, Denise J Montell.

  Proteotoxic stress drives numerous degenerative diseases. Cells initially adapt to misfolded proteins by activating the unfolded protein response (UPR), including endoplasmic-reticulum-associated protein degradation (ERAD). However, persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. The ER-localized Zn2+ transporter ZIP7 is conserved from plants to humans and required for intestinal self-renewal, Notch signaling, cell motility, and survival. However, a unifying mechanism underlying these diverse phenotypes was unknown. In studying Drosophila border cell migration, we discovered that ZIP7-mediated Zn2+ transport enhances the obligatory deubiquitination of proteins by the Rpn11 Zn2+ metalloproteinase in the proteasome lid. In human cells, ZIP7 and Zn2+ are limiting for deubiquitination. In a Drosophila model of neurodegeneration caused by misfolded rhodopsin (Rh1), ZIP7 overexpression degrades misfolded Rh1 and rescues photoreceptor viability and fly vision. Thus, ZIP7-mediated Zn2+ transport is a previously unknown, rate-limiting step for ERAD in vivo with therapeutic potential in protein misfolding diseases.

Keywords:  Drosophila; ER stress; ERAD; apoptosis; border cell migration; integrated stress response; neurodegeneration; proteasome; retinitis pigmentosa; zinc transport

DOI:  https://doi.org/10.1016/j.devcel.2024.04.003
J Cell Mol Med. 2024 May;28(9): e18259

Irisin attenuates ventilator-induced diaphragmatic dysfunction by inhibiting endoplasmic reticulum stress through activation of AMPK.

Jumei Zhang, Rui Tu, Fasheng Guan, Jianguo Feng, Jing Jia, Jun Zhou, Xiaobin Wang, Li Liu.

  Mechanical ventilation (MV) is an essential life-saving technique, but prolonged MV can cause significant diaphragmatic dysfunction due to atrophy and decreased contractility of the diaphragm fibres, called ventilator-induced diaphragmatic dysfunction (VIDD). It is not clear about the mechanism of occurrence and prevention measures of VIDD. Irisin is a newly discovered muscle factor that regulates energy metabolism. Studies have shown that irisin can exhibit protective effects by downregulating endoplasmic reticulum (ER) stress in a variety of diseases; whether irisin plays a protective role in VIDD has not been reported. Sprague-Dawley rats were mechanically ventilated to construct a VIDD model, and intervention was performed by intravenous administration of irisin. Diaphragm contractility, degree of atrophy, cross-sectional areas (CSAs), ER stress markers, AMPK protein expression, oxidative stress indicators and apoptotic cell levels were measured at the end of the experiment.Our findings showed that as the duration of ventilation increased, the more severe the VIDD was, the degree of ER stress increased, and the expression of irisin decreased.ER stress may be one of the causes of VIDD. Intervention with irisin ameliorated VIDD by reducing the degree of ER stress, attenuating oxidative stress, and decreasing the apoptotic index. MV decreases the expression of phosphorylated AMPK in the diaphragm, whereas the use of irisin increases the expression of phosphorylated AMPK. Irisin may exert its protective effect by activating the phosphorylated AMPK pathway.

Keywords:  AMPK; diaphragmatic dysfunction; endoplasmic reticulum stress; irisin; mechanical ventilation; oxidative stress

DOI:  https://doi.org/10.1111/jcmm.18259
Trends Endocrinol Metab. 2024 Apr 24. pii: S1043-2760(24)00089-4. [Epub ahead of print]

Chemical chaperones in metabolic fitness beyond protein folding.

Ester Zito, Alain Lescure, Nica Borgese.

  Chemical chaperones are small molecules that improve protein folding, alleviating aberrant pathological phenotypes due to protein misfolding. Recent reports suggest that, in parallel with their role in relieving endoplasmic reticulum (ER) stress, chemical chaperones rescue mitochondrial function and insulin signaling. These effects may underlie their pharmacological action on metabolically demanding tissues.

Keywords:  PBA; TUDCA; chemical chaperone; congenital myopathies; insulin signaling; metabolic disease; misfolding disease

DOI:  https://doi.org/10.1016/j.tem.2024.04.006
Nat Commun. 2024 Apr 25. 15(1): 3481

Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice.

Junying Wang, Wenting Lu, Jerry Zhang, Yong Du, Mingli Fang, Ao Zhang, Gabriel Sungcad, Samantha Chon, Junji Xing.

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

DOI: https://doi.org/10.1038/s41467-024-44745-x
bioRxiv. 2024 Apr 20. pii: 2024.04.16.589737. [Epub ahead of print]

PERK inhibition in zebrafish mimics human Wolcott-Rallison syndrome phenotypes.

Liliana M Almeida, Leonor Pereira Lima, Nuno A S Oliveira, Rui F O Silva, Bruno Sousa, José Bessa, Brígida R Pinho, Jorge M A Oliveira.

Wolcott-Rallison Syndrome (WRS) is the most common cause of permanent neonatal diabetes mellitus among consanguineous families. The diabetes associated with WRS is non-autoimmune, insulin-requiring and associated with skeletal dysplasia and growth retardation. The therapeutic options for WRS patients rely on permanent insulin pumping or on invasive transplants of liver and pancreas. WRS has a well identified genetic cause: loss-of-function mutations in the gene coding for an endoplasmic reticulum kinase named PERK (protein kinase R-like ER kinase). Currently, WRS research is facilitated by cellular and rodent models with PERK ablation. While these models have unique strengths, cellular models incompletely replicate the organ/system-level complexity of WRS, and rodents have limited scalability for efficiently screening potential therapeutics. To address these challenges, we developed a new in vivo model of WRS by pharmacologically inhibiting PERK in zebrafish. This small vertebrate displays high fecundity, rapid development of organ systems and is amenable to highly efficient in vivo drug testing. PERK inhibition in zebrafish produced typical WRS phenotypes such as glucose dysregulation, skeletal defects, and impaired development. PERK inhibition in zebrafish also produced broad-spectrum WRS phenotypes such as impaired neuromuscular function, compromised cardiac function and muscular integrity. These results show that zebrafish holds potential as a versatile model to study WRS mechanisms and contribute to the identification of promising therapeutic options for WRS.

DOI: https://doi.org/10.1101/2024.04.16.589737