bims-unfpre 2025-10-05 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–10–05
ten papers selected by
Susan Logue, University of Manitoba

RIP3 and MLKL regulate Hepatic ER stress in alcohol-associated liver disease and pharmacological ER stress models: insights beyond necroptosis.
ER stress tolerance is regulated by copper-dependent PERK kinase activity.
Regulation of the PERK pathway attenuates hypoxia-induced apoptosis in a 661W photoreceptor cell model.
BAP31 represses endoplasmic reticulum stress-mediated apoptosis and alleviates neurodegeneration in Parkinson's disease.
A FMRF-amide peptide that regulates cell non-autonomous protein homeostasis in C. elegans.
ER stress upregulates S100A11 in steatohepatitis models via epigenetic modifications within the lipotoxicity influenced enhancer.
The effect of HNF4α knockout in beta cells is age and sex dependent.
ER stress sensor PERK promotes T-cell pathogenicity in GVHD by regulating ER-associated degradation.
Importance of PERK pathway modulation on colorectal cancer management: a systematic review.
ER shaping closes the gap in wound healing.

bioRxiv. 2025 Sep 25. pii: 2025.09.24.677754. [Epub ahead of print]

RIP3 and MLKL regulate Hepatic ER stress in alcohol-associated liver disease and pharmacological ER stress models: insights beyond necroptosis.

Rakesh K Arya, Emily Huang, Megan R McMullen, Kyle L Poulsen, Jianguo Wu, Jared Travers, Evi Paouri, Dimitrios Davalos, Laura E Nagy.

Background and Aim: Endoplasmic reticulum (ER) stress is an important contributor to liver disease progression, including alcohol-associated liver disease (ALD). While receptor-interacting protein kinase-3 (RIP3) and mixed lineage kinase domain-like pseudokinase (MLKL) are known for their roles in necroptosis, emerging evidence highlights their non-canonical functions in metabolic regulation and cellular stress responses. However, their specific role in regulating hepatic ER stress remains unclear. This study investigates how RIP3, its kinase activity, and MLKL regulate ER stress pathways during chronic ethanol exposure and pharmacological ER stress induction.
Methods: Rip3 -/- , Rip3 K51A/K51A and Mlkl -/- mice alongside WT controls and pharmacological necroptosis inhibitors were used to study the role of RIP3 and MLKL in modulating ER stress. Chronic ethanol feeding and pharmacological agents (tunicamycin, thapsigargin) were utilized to induce ER stress in vivo and in isolated primary hepatocytes. ER stress markers were assessed by qPCR and western blot, ER expansion was evaluated by confocal microscopy, and hepatocyte viability was measured using MTS assay.
Results: Chronic ethanol increased expression of ER stress markers in WT mice; this response was attenuated in Rip3 -/- mice. Tunicamycin exposure increased hepatic ER stress markers in WT mice; this response was diminished in Rip3 -/- , Rip3 K51A/K51A and Mlkl -/- mice. In primary hepatocytes, genetic and pharmacological inhibition of RIP3 and MLKL also reduced thapsigargin-induced ER stress responses. Hepatocytes isolated from Rip3 -/- , Rip3 K51A/K51A and Mlkl -/- mice exhibited enhanced cell viability under ER stress conditions compared to hepatocytes from WT mice, which was associated with ER expansion as a potential mechanism for mitigating ER stress.
Conclusion: This study highlights a novel function of RIP3 and MLKL in regulating hepatic ER stress responses, expanding their known roles beyond programmed necrosis.
Impact and Implications: This study provides new mechanistic insight into how RIP3 and MLKL regulate hepatic ER stress responses, extending their roles beyond necroptosis. By demonstrating that genetic or pharmacological inhibition of Rip3 , RIP3 kinase activity and Mlkl attenuates ER stress signaling, reduces cell death, and promotes adaptive ER remodeling, our findings identify these proteins as key modulators of hepatocyte survival under stress. These results are important for researchers and clinicians focused on alcohol-associated liver disease and other ER stress-driven liver disorders, as they highlight novel therapeutic targets. In practical terms, modulation of the RIP3- MLKL axis could inform the development of interventions aimed at enhancing ER stress resilience, with potential applications in drug development for ER stress-associated liver injury.

DOI: https://doi.org/10.1101/2025.09.24.677754
Cell Rep. 2025 Sep 25. pii: S2211-1247(25)01089-7. [Epub ahead of print]44(10): 116318

ER stress tolerance is regulated by copper-dependent PERK kinase activity.

Sarah E Bond Newton, Xinglong Shi, Noah R Beratan, Julia Perhacs, Jitendra K Arya, Margaret K Bond, Tali Gidalevitz, Cagla Akay-Espinoza, Donita C Brady, Kelly L Jordan-Sciutto.

  Pancreatic/PKR-like endoplasmic reticulum (ER) kinase (PERK) is a kinase that, in response to ER stress, mediates dual homeostatic and pro-apoptotic signaling. Thus, intricate regulation is required for physiological function. Attempts to modulate PERK activity have shown that the determinants of adaptive vs. maladaptive signaling remain ambiguous. Here, with purified protein, we provide evidence that PERK binds copper, identifies residues required for interaction, and demonstrates that copper is necessary for kinase activity. Furthermore, cellular PERK activity can be modulated via copper availability, and this regulatory relationship can be manipulated to dictate ER stress tolerance. Critically, these phenomena translate to phenotypes in vivo, as C. elegans harboring a "PERK-copper mutant" exhibit exacerbated ER-stress sensitivity. The copper-PERK paradigm suggests that copper homeostasis, as a regulator of PERK, may constitute a critical factor in resolving the long-standing ambiguity in endeavors to therapeutically target PERK.

Keywords:  CP: Cell biology; ER stress; ISR; PERK; UPR; copper; kinase regulation; stress tolerance

DOI:  https://doi.org/10.1016/j.celrep.2025.116318
Exp Eye Res. 2025 Oct 01. pii: S0014-4835(25)00439-7. [Epub ahead of print] 110667

Regulation of the PERK pathway attenuates hypoxia-induced apoptosis in a 661W photoreceptor cell model.

Xingxing Zheng, Cong Han, Keke Ge, Zhi Li, Peirun Wu, Xinran Yu, Yilan Lu, Yi Yang, Wenfang Zhang.

  High-altitude retinopathy (HAR), characterized by retinal dysfunction under hypobaric hypoxia, remains mechanistically unclear. This study explored hypoxia-induced molecular injury in retinal photoreceptor cells using a hypoxic 661W cell model and identified potential therapeutic targets. Hypoxia triggered endoplasmic reticulum (ER) stress in 661W photoreceptor cells, marked by increased phosphorylation of PERK and eIF2α, upregulation of ATF4, and elevated CHOP expression. Both Salubrinal (Sal) and PERK-targeting siRNAs (PERK-siRNAs) attenuated ER stress via the PERK/eIF2α/ATF4/CHOP pathway, reducing apoptosis and reactive oxygen species (ROS) production by suppressing HIF-1α. Sal further preserved ER morphology, alleviating ultrastructural abnormalities such as ER dilation and mitochondrial swelling observed via transmission electron microscopy. In a HAR mouse model under simulated 5,000 m altitude conditions, Sal improved retinal function, as evidenced by enhanced a- and b-wave amplitudes in electroretinogram (ERG) recordings. These findings suggest that ER stress modulation through PERK pathway inhibition mitigates hypoxia-induced retinal damage, highlighting its potential as a therapeutic strategy for HAR and related retinal disorders.

Keywords:  Electroretinogram; Endoplasmic reticulum stress; High-altitude retinopathy; Hypobaric hypoxia; Transmission electron microscopy

DOI:  https://doi.org/10.1016/j.exer.2025.110667
Cell Death Dis. 2025 Sep 29. 16(1): 672

BAP31 represses endoplasmic reticulum stress-mediated apoptosis and alleviates neurodegeneration in Parkinson's disease.

Yan Qin, Ying Chen, Minghao Chi, Junzhen Jia, Li Wang, Yan Zhao, Zhecheng Wang, Junjun Zhou, Jihong Yao.

Excessive endoplasmic reticulum (ER) stress and neuronal apoptosis contribute to neurodegeneration in Parkinson's disease (PD). However, the molecular mechanisms underlying these perturbations and how they are directly regulated remain unclear. B cell receptor-associated protein 31 (BAP31), which is highly expressed in the ER, has been shown to participate mainly in regulating ER stress and apoptosis. Here, our results showed that BAP31 expression was dramatically decreased in PD. Notably, overexpression of BAP31 exerted neuroprotective effects by inhibiting ER stress and apoptosis in vitro and in vivo, whereas BAP31 siRNA strongly abolished these effects. Interestingly, 4-phenylbutyric acid (4-PBA), the ER stress inhibitor, reversed the detrimental effect of BAP31 knockdown in vitro. Mutations in PTEN-induced putative kinase 1 (PINK1) are known to cause autosomal recessive early-onset PD. PINK1 has been implicated in protein phosphorylation pathways that are associated with ER stress and apoptosis. Bioinformatics analysis and our results demonstrated that PINK1 interacts with BAP31 and phosphorylates it at the Ser 142 residue. Furthermore, the protective effects of PINK1 overexpression against ER stress-mediated apoptosis were abolished by BAP31 interference or BAP31-S142A and strengthened by BAP31-S142E. Overall, the present study suggests that BAP31 overexpression exerts neuroprotective effects by inhibiting ER stress-induced apoptosis. Regulation of the PINK1/BAP31 pathway may be a beneficial strategy for PD.

DOI: https://doi.org/10.1038/s41419-025-07907-3
bioRxiv. 2025 Mar 15. pii: 2025.03.14.643343. [Epub ahead of print]

A FMRF-amide peptide that regulates cell non-autonomous protein homeostasis in C. elegans.

Carrie A Sheeler, Jacqueline Y Lo, Daviana Menendez Escalera, Emmett Griffin-Baldwin, Karmen Mah, Adam Roszczyk, Antoine E Roux, Cynthia Kenyon, Jennifer L Garrison, Ashley E Frakes.

The coordination of protein homeostasis from the brain to periphery is essential for the health and survival of all animals. In C. elegans , glia serve a central role in coordinating organismal protein homeostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPR ER ). However, the full extent of the cell non-autonomous response and the identity of the signaling molecules required remained unknown. Here, we show that glial UPR ER activation induces robust transcriptomic changes in specific tissue types across the animal, particularly in pathways related to neuropeptide signaling. We performed neuropeptidomics and loss and gain-of-function genetic screens and identified a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPR ER . FLP-17 is sufficient to protect against chronic ER stress and age-dependent protein aggregation. We determined that FLP-17 acts through the receptor, EGL-6, to activate cell non-autonomous UPR ER . This work reveals a complex peptidergic signaling network initiated by glial activation of the UPR ER to regulate organismal protein homeostasis.

DOI: https://doi.org/10.1101/2025.03.14.643343
J Clin Invest. 2025 Sep 30. pii: e191074. [Epub ahead of print]

ER stress upregulates S100A11 in steatohepatitis models via epigenetic modifications within the lipotoxicity influenced enhancer.

P Vineeth Daniel, Hanna L Erickson, Daheui Choi, Feda H Hamdan, Yasuhiko Nakao, Gyanendra Puri, Takahito Nishihara, Yeriel Yoon, Amy S Mauer, Debanjali Dasgupta, Jill Thompson, Alexander Revzin, Harmeet Malhi.

  Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by complex interactions between lipotoxicity, ER stress responses, and immune-mediated inflammation. We identified enrichment of the proinflammatory alarmin S100 calcium-binding protein A11 (S100A11) on extracellular vesicles stimulated by palmitate-induced lipotoxic ER stress with concomitant upregulation of hepatocellular S100A11 abundance in an IRE1A-XBP1s dependent manner. We next investigated the epigenetic mechanisms that regulate this stress response. Publicly available human liver ChIP-Seq GEO datasets demonstrated a region of histone H3 lysine 27 (H3K27) acetylation upstream to the S100A11 promoter. H3K27acetylation ChIP-qPCR demonstrated a positive correlation between lipotoxic ER stress and H3K27acetylation of the region, which we termed Lipotoxicity Influenced Enhancer (LIE) domain. CRISPR-mediated repression of the LIE domain reduced palmitate-induced H3K27acetylation and corresponding S100A11 upregulation in Huh7 cells and immortalized mouse hepatocytes. Silencing of the murine LIE in two independent steatohepatitis models demonstrated reduced S100a11 upregulation and attenuated liver injury. We confirmed H3K27acetylation and XBP1s occupancy at the LIE domain in human MASH liver samples and an increase in hepatocyte-derived S100A11-enriched extracellular vesicles in MASH patient plasma. Our studies demonstrate a LIE domain which mediates hepatic S100A11 upregulation. This pathway may be a potential therapeutic target in MASH.

Keywords:  Epigenetics; Hepatology; Inflammation; Metabolism

DOI:  https://doi.org/10.1172/JCI191074
Islets. 2025 Dec 31. 17(1): 2552549

The effect of HNF4α knockout in beta cells is age and sex dependent.

Catharina B P Villaca, Viviane R Oliveira, Gustavo J Santos, Fernanda Ortis.

  HNF4α is important for beta cells' ability to adequately secrete insulin in response to glucose concentration and endoplasmic reticulum (ER) homeostasis. In humans, HNF4α mutations are responsible for Diabetes mellitus subtype MODY1, which has an age-determining onset. Additionally, in other forms of DM, there is evidence that sex can influence beta cell dysfunction, with possible involvement of ER stress pathways. Thus, we assessed the influence of sex and age on beta-cell dysfunction induced by HNF4α absence. We used an animal model with specific beta cells KO of HNF4α, induced after birth (Ins. CRE HNF4αloxP/loxP). Glucose intolerance is observed after 10 d of KO induction, at 50 d of age, with KO males (MKO) displaying more severe glucose intolerance than KO females (FKO). The percentage of insulin-positive cells in KO mice islets is lower compared to Control at all ages evaluated, with MKO mice showing a more pronounced decline at later ages compared to FKO. Both KO groups exhibited reduced beta cell mass and increased α-cell mass, which was more pronounced in MKO. ER stress was induced in both KO groups; however, ER stress-mediated apoptosis was observed only in MKO. FKO mice show evidence of beta cell differentiated state loss. In summary, beta cell loss in HNF4α-KO is influenced by sex and age, involves induction of ER stress, and is more severe in males, where ER stress-induced beta cell death is observed. Partial protection observed in females seems to involve dedifferentiation of beta cells.

Keywords:  Diabetes mellitus; HNF4α; apoptosis; beta cell; dedifferentiation

DOI:  https://doi.org/10.1080/19382014.2025.2552549
J Clin Invest. 2025 Sep 30. pii: e190958. [Epub ahead of print]

ER stress sensor PERK promotes T-cell pathogenicity in GVHD by regulating ER-associated degradation.

Qiao Cheng, Hee-Jin Choi, Yongxia Wu, Xiaohong Yuan, Allison Pugel, Linlu Tian, Michael Hendrix, Denggang Fu, Reza Alimohammadi, Chen Liu, Xue-Zhong Yu.

  Endoplasmic reticulum (ER) stress through IRE1/XBP-1 is implicated in the onset and progression of graft-versus-host disease (GVHD), but the role of ER stress sensor PERK in T-cell allogeneic responses and GVHD remains unexplored. Here, we report that PERK is a key regulator in T-cell allogeneic response and GVHD induction. PERK augments GVHD through increasing Th1 and Th17 population, while reducing Treg differentiation by activating Nrf2 pathway. Genetical deletion or selective inhibition of PERK pharmacologically reduces GVHD while preserving graft-versus-leukemia (GVL) activity. At cellular level, PERK positively regulates CD4+ T-cell pathogenicity, while negatively regulating CD8+ T-cell pathogenicity in the induction of GVHD. At molecular level, PERK interacts with SEL1L and regulates SEL1L expression, leading to augmented T-cell allogeneic responses and GVHD development. In vivo, PERK deficiency in donor T cells alleviate GVHD through ER-associated degradation (ERAD). Furthermore, pharmacological inhibition of PERK with AMG44 significantly suppresses the severity of GVHD induced by murine or human T cells. In summary, our findings validate PERK as a potential therapeutic target for the prevention of GVHD while preserving GVL responses, and uncover the mechanism by which PERK differentially regulates CD4+ versus CD8+ T-cell allogeneic and anti-tumor responses.

Keywords:  Bone marrow transplantation; Immunology; Inflammation

DOI:  https://doi.org/10.1172/JCI190958
BMC Cancer. 2025 Oct 03. 25(1): 1502

Importance of PERK pathway modulation on colorectal cancer management: a systematic review.

Marzieh Nemati, Sanaz Dastghaib, Zahra Hosseinzadeh, Mina Molayem, Morvarid Siri, Bahareh Ebrahimi, Zohreh Bagheri.

   BACKGROUND: The protein kinase RNA-like endoplasmic reticulum kinase (PERK) branch of the Unfolded Protein Response (UPR) plays a complex and context-dependent role in the colorectal cancer (CRC). While some studies indicate that PERK activation suppresses tumor growth by inducing apoptosis and limiting proliferation, others suggest that it may promote tumor progression by supporting cancer cell survival under stress. This systematic review aims to clarify the dual role of PERK signaling in CRC and evaluate its potential as a therapeutic target.
METHODS: We included full-text English-language studies investigating the role of PERK signaling in CRC using in vitro and/or animal models. Studies on non-CRC malignancies or unrelated mechanisms were excluded. Searches were conducted in PubMed, Web of Science (WOS), and Scopus using relevant keywords.
RESULTS: A total of 395 articles were initially identified. After removing duplicates (n = 173), review articles (n = 11), and unrelated studies (n = 66), 45 studies met the inclusion criteria. Most of these (n = 36) used in vitro models, with the HCT-116 cell line being the most frequently used (n = 19). While most studies (n = 36) reported anti-tumorigenic effects associated with PERK activation, several identified conditions under which PERK signaling may support tumor progression. These conflicting findings may be attributed to differences in experimental models, PERK modulation strategies, and endoplasmic reticulum stress induction methods.
CONCLUSIONS: This review highlights the dual and context-dependent nature of PERK pathway activation in CRC. Although PERK often appears to exert tumor-suppressive effects, evidence also points to its tumor-promoting potential under certain conditions. A nuanced understanding of these roles is crucial for developing PERK-targeted therapies in CRC.
TRIAL REGISTRATION: This systematic review has been registered in PROSPERO (International Prospective Register of Systematic Reviews) with the registration number CRD42023241342.

Keywords:  Colorectal cancer; Endoplasmic reticulum stress; Protein kinase RNA like endoplasmic reticulum kinase; Unfolded protein response

DOI:  https://doi.org/10.1186/s12885-025-14952-w
Nat Cell Biol. 2025 Sep 30.

ER shaping closes the gap in wound healing.

Craig Blackstone.

DOI: https://doi.org/10.1038/s41556-025-01779-7