bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–03–22
ten papers selected by
Susan Logue, University of Manitoba
  1. Bip1 regulates AMPK signaling in response to endoplasmic reticulum stress.
  2. Calcium-mediated calreticulin-IRE1α interaction drives dynamic fluctuation of IRE1α activity under chronic endoplasmic reticulum stress.
  3. ER Stress-Induced β-Cell Apoptosis is Linked to Novel Select Lipid Signaling at the Transcriptional Level: Implications in T1D Developmen t.
  4. UFMylation: A Key Role in Maintaining Endoplasmic Reticulum Homeostasis.
  5. Magnaporthe oryzae MoPh1 perceives ER stress and promotes adaptive responses via a plasma membrane-to-vacuole pathway.
  6. PERK Deficiency Amplifies Molecular, Structural, and Network Vulnerability to Repetitive Mild Traumatic Brain Injury.
  7. ALG6 orchestrates coronavirus replication via the endoplasmic reticulum stress-autophagy axis.
  8. Cisplatin-associated transcriptional changes in ER stress-related genes in skeletal muscle and C2C12 myotubes.
  9. Potential gonadal-beneficial effect of sitagliptin against paclitaxel-induced testicular dysfunction via mediating PERK/CHOP/NLRP3/Sestrin2 signaling pathway.
  10. Lipid overload triggers PERK-ALCAT1-mediated mitophagy failure in hepatocytes.
  1. FEBS J. 2026 Mar 18.
    Bip1 regulates AMPK signaling in response to endoplasmic reticulum stress.
    Mengdan Zhu, Chuanhai Fu.
      The accumulation of misfolded and unfolded proteins within the endoplasmic reticulum (ER) lumen induces ER stress, which in turn triggers various consequences, such as the unfolded protein response (UPR). AMP-activated protein kinase (AMPK) is also a cellular stress sensor. However, the interplay between AMPK and ER stress remains poorly understood. In this study, we report that in the fission yeast Schizosaccharomyces pombe, the deletion of erd2, a central component for the retrieval of ER-resident proteins, leads to the accumulation of the canonical ER luminal chaperone Bip1 in the cytosol. Moreover, we demonstrate that erd2 deletion increases the levels of the AMPK upstream kinase Ssp1 in a Bip1-dependent manner, thereby promoting AMPK phosphorylation. Intriguingly, although these phenotypes are not dependent on UPR, they can also be caused by ER stress. We further identify multiple E3 ubiquitin ligases that are responsible for the regulation of Ssp1 stability, and Bip1 physically interacts with and stabilises Ssp1 by inhibiting ubiquitination of Ssp1. Additionally, we elucidate that AMPK activation, mediated by the stabilised Ssp1, is required to sustain cell viability, particularly in cells lacking Erd2. Collectively, our findings demonstrate the important role of Erd2 in the maintenance of cellular homeostasis and establish a link between ER stress and AMPK signalling.
    Keywords:  AMPK; Bip1; Erd2; Schizosaccharomyces pombe; Ssp1
    DOI:  https://doi.org/10.1111/febs.70496
  2. Nat Commun. 2026 Mar 17.
    Calcium-mediated calreticulin-IRE1α interaction drives dynamic fluctuation of IRE1α activity under chronic endoplasmic reticulum stress.
    Jianwei Cao, Xudong Zhao, Yunxin Xu, Chen Yang, Yazhen Huo, Ting Li, Wenjia Gu, Lei Wang, Youjun Wang, Likun Wang.
      The unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress can be both pro-survival or pro-apoptotic, depending on the duration and intensity of the stress. ER stress under (patho)physiological conditions can last for long time, yet the dynamic regulation of the UPR under prolong ER stress is largely unknown. Here, we characterized the UPR dynamics during pharmacologically induced long-term ER stress and revealed an "up-down-up" fluctuation pattern of the IRE1α signal in various types of cells. A fluctuation of the calreticulin-IRE1α interaction intensity orchestrates dynamic regulation of IRE1α activity, which negatively correlates with the intensity of the interaction between IRE1α and BIP, a known suppressor of IRE1α. The calreticulin-IRE1α interaction is negatively affected by Ca2+ concentration, which showed "down-up-down" pattern in the ER lumen over time. Furthermore, a circadian rhythmic fluctuation of calreticulin-IRE1α interaction intensity is observed in mouse liver, accompanied by oscillation of IRE1α phosphorylation level at regular physiological conditions. Our study suggests a calcium-mediated, calreticulin-driven IRE1α activity fluctuation, representing an intermediate status that the cell adopts to cope with chronic ER stress that may exist under both pathophysiological and physiological conditions.
    DOI:  https://doi.org/10.1038/s41467-026-70679-7
  3. bioRxiv. 2026 Mar 06. pii: 2026.03.02.708596. [Epub ahead of print]
    ER Stress-Induced β-Cell Apoptosis is Linked to Novel Select Lipid Signaling at the Transcriptional Level: Implications in T1D Developmen t.
    Xiaoyong Lei, Anil K Challa, Susan E Nozell, Tomader Ali, Daniel J Stephenson, Andrew Nafzinger, Chad S Hunter, Adam R Wende, Ernesto S Nakayasu, Ying Gai-Tusing, Charles E Chalfant, Sasanka Ramanadham.
      Type 1 diabetes (T1D) is a consequence of β-cell death. ER stress precedes T1D onset and prolonged ER stress in β-cells can lead to β-cell apoptosis. We reported that lipid signaling generated by the Ca 2+ -independent phospholipase A 2 β (iPLA 2 β), encoded by Pla2g6 , participates in ER stress-mediated β-cell apoptosis. β-Cell membranes are enriched in arachidonic acid containing glycerophospholipids and the iPLA 2 β catalyzes the hydrolysis of arachidonic acid in ER stressed β-cells. Metabolism of arachidonic acid leads to the generation of various proinflammatory lipids, raising the possibility that they contribute to ER stress and β-cell death leading to T1D. However, molecular mechanisms by which such β-cell-iPLA 2 β-derived lipid (iDL) signaling contributes to β-cell apoptosis are not understood. It is well known that ER stress-mediated β-cell apoptosis is associated with induction of transcription factors, NFκB and STAT1. We report here that both induce Pla2g6 and, unexpectedly, we find that iPLA 2 β, which lacks DNA-binding motifs, associates with NFkB , Stat1 , and Pla2g6 promoter regions. Consistently, p65-NFκB and pSTAT1 induction is reduced with select inhibition or knockdown of iPLA 2 β. Surprisingly, iPLA 2 β expression is also reduced by select inhibition of iPLA 2 β, raising the possibility of feedback regulation by iDLs. In support, we find that select iDLs, recognized to be proinflammatory, enhance association of iPLA 2 β with Pla2g6 , Nfkb , and Stat1 promoter regions leading to induction of all three gene products and β-cell apoptosis. Our findings reveal previously unrecognized transcriptional regulation by iDL signaling and, iPLA 2 β itself, that leads to gene products that promote β-cell apoptosis. Analogous findings in human islets validate this mechanism raising the possibility that targeting select lipid signaling can reduce ER stress in β-cells and ameliorate T1D development.
    DOI:  https://doi.org/10.64898/2026.03.02.708596
  4. FASEB J. 2026 Mar 31. 40(6): e71710
    UFMylation: A Key Role in Maintaining Endoplasmic Reticulum Homeostasis.
    Kang Zheng, Yi Ai, Junlin Yang, Mengsheng Qiu.
      UFMylation, a ubiquitin-like post-translational modification system, plays an essential role in regulating endoplasmic reticulum (ER) function. This process involves a cascade of biochemical reactions mediated by several core molecular components, including UFM1, the E1 enzyme UBA5, the E2 enzyme UFC1, the E3 enzyme UFL1, as well as the accessory proteins DDRGK1 and CDK5RAP3. During UFMylation, UFM1 undergoes maturation, activation, conjugation, and deconjugation in a dynamic process, whereas the ER-localized UFL1-DDRGK1 complex governs substrate selection and modification efficiency. The major function of UFMylation is to modulate the ER stress response, thereby balancing adaptive cellular remodeling and apoptotic signaling. Through the modification of key substrate proteins, UFMylation activates a synergistic clearance mechanism that coordinates ER-phagy with ribosome-associated quality control, thereby facilitating the removal of stalled ribosomes and damaged ER to maintain ER proteostasis and structural integrity. Dysregulation of UFMylation is frequently associated with various diseases characterized by abnormal ER function. In this review, we will describe the molecular pathways associated with ER-associated UFMylation process and then discuss its core regulatory functions within the ER and its possible involvements in several congenital human diseases.
    DOI:  https://doi.org/10.1096/fj.202504650RR
  5. Nat Commun. 2026 Mar 16.
    Magnaporthe oryzae MoPh1 perceives ER stress and promotes adaptive responses via a plasma membrane-to-vacuole pathway.
    Ziyi Yin, Jiayun Xu, Shijie Ma, Jiazong Liu, Tianfeng Zhao, Yuanchen Li, Yi Wang, Chunyan Liu, Ziming Wang, Yanke Jiang, Haimiao Zhang, Chongchong Lu, Yingying Qin, Ziying Kong, Shi-En Lu, Congming Lu, Yang Li, Xinhua Ding.
      During growth and development, cells experience both internal and external stresses, which can exert harmful impacts if they are poorly managed. Endoplasmic reticulum (ER) stress is an internal stress that is induced when protein misfolding or perturbations occur at excess rates, and the conventional response pathways from the ER to the nucleus are activated to address the stress. However, the involvement of the plasma membrane (PM) system in response to this internal stress has been insufficiently investigated. Here, a PM sensor, MoPh1, was observed to perceive stress through ER-PM contact sites and target the autophagosome and vacuole, consequently stimulating the autophagy process and supporting stress relief. The PM-to-vacuole pathway mediated by MoPh1 is independent of the classical ER-to-nucleus pathway and might be highly important in both fungi and plants, as it plays a crucial role in alleviating ER stress and promoting cellular adaptation for cell survival.
    DOI:  https://doi.org/10.1038/s41467-026-70610-0
  6. bioRxiv. 2026 Mar 06. pii: 2026.03.04.709563. [Epub ahead of print]
    PERK Deficiency Amplifies Molecular, Structural, and Network Vulnerability to Repetitive Mild Traumatic Brain Injury.
    Marangelie Criado-Marrero, Sakthivel Ravi, Daylin Barroso, Tristyn N Garza, Diana M Cuestas Torres, Christian Lessard, Juan Pablo Castano, MacKenzie L Bolen, Uriel Rubinovich, Stefan Prokop, Paramita Chakrabarty, Laura P W Ranum, Marcelo Febo, Jose Francisco Abisambra.
      Repetitive mild traumatic brain injury (rmTBI) produces cumulative cellular stress that can lead to progressive brain dysfunction, yet the mechanisms governing vulnerability to repeated injury remain unclear. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) regulates cellular proteostasis through the unfolded protein response and is implicated in neurodegeneration and acute brain injury. Here, we directly tested the role of PERK deficiency in shaping the brain's response to rmTBI. Using a mouse model of neuronal PERK deficiency, we combined spatial proteomics and tissue analyses with resting-state functional MRI and diffusion tensor imaging to assess molecular, functional, and structural outcomes after rmTBI. PERK deficiency increased susceptibility to rmTBI-induced disruption of protein homeostasis, altered large-scale functional connectivity, and exacerbated white matter microstructural changes consistent with axonal and myelin damage. Molecular alterations were spatially aligned with imaging-defined network and white matter abnormalities. These findings identify PERK signaling as a key determinant of brain resilience to repetitive mild injury and link ER stress dysregulation to network-level dysfunction following rmTBI.
    DOI:  https://doi.org/10.64898/2026.03.04.709563
  7. Cell Rep. 2026 Mar 17. pii: S2211-1247(26)00186-5. [Epub ahead of print]45(4): 117108
    ALG6 orchestrates coronavirus replication via the endoplasmic reticulum stress-autophagy axis.
    Yanan Fu, Meijie Gao, Zhen Fu, Limeng Sun, Zhelin Su, Yubei Tan, Yixin Xiang, Yuejun Shi, Shengsong Xie, Guiqing Peng.
      Coronaviruses (CoVs) constitute a major global health threat, and their replication is inseparable from host factors. Investigating host-virus interactions is critical for elucidating the CoV life cycle. Here, we identify alpha-1,3-glucosyltransferase (ALG6) as an essential host factor for CoV replication. Mechanistically, its catalytic activity governs transmissible gastroenteritis virus (TGEV) replication, and ALG6 knockout (KO) inhibits viral entry by downregulating the receptor aminopeptidase N (ANPEP). Moreover, our results indicate that ALG6 KO triggers endoplasmic reticulum (ER) stress, resulting in suppressed viral replication. Further investigations demonstrate that ALG6 KO predominantly hinders viral replication by triggering downstream autophagy induced by ER stress. Transmission electron microscopy analysis reveals that ALG6 KO disrupts the formation of double-membrane vesicles (DMVs) during the initial stages of viral replication. In summary, our findings underscore the crucial role of ALG6 in the replication of CoVs, presenting a promising avenue for the development of potential therapeutic strategies against future CoV infections.
    Keywords:  ALG6; CP: microbiology; ER stress; autophagy; coronavirus; replication
    DOI:  https://doi.org/10.1016/j.celrep.2026.117108
  8. Toxicol Mech Methods. 2026 Mar 16. 1-9
    Cisplatin-associated transcriptional changes in ER stress-related genes in skeletal muscle and C2C12 myotubes.
    Hayato Nanri, Hiroyasu Sakai, Shinki Soga, Yuya Chigusa, Ryunosuke Ichikawa, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Kumiko Ogawa.
      Cisplatin is a widely used chemotherapeutic drug that causes severe side effects, including skeletal muscle atrophy; however, the cellular responses of skeletal muscle to cisplatin exposure remain incompletely characterized. This study aimed to comparatively characterize cisplatin-associated transcriptional responses in skeletal muscle in vivo and in vitro. Male mice receiving intraperitoneal cisplatin administration (3 mg/kg/day for four consecutive days) exhibited significant quadriceps muscle loss on day 4, accompanied by increased expression of the muscle-specific ubiquitin ligase genes MuRF1 and atrogin-1. Consistently, cisplatin-treated C2C12 myotubes showed elevated mRNA expression of these atrophy-related genes. In addition, multiple endoplasmic reticulum (ER) stress-related genes, including Ddit3/CHOP, Atf4, Hspa5/Bip, and Ppp1r15a/GADD34, were significantly upregulated in both models. Notably, the spliced form of Xbp1 was differentially regulated, being increased in mouse skeletal muscle but decreased in C2C12 myotubes, indicating model-dependent ER stress-associated transcriptional responses. These findings demonstrate that cisplatin exposure is associated with coordinated changes in atrophy- and ER stress-related gene expression in skeletal muscle and highlight important differences between in vivo and in vitro models that should be considered when evaluating cisplatin-associated skeletal muscle toxicity.
    Keywords:  C2C12 myotubes; Cisplatin; ER stress; Xbp1; skeletal muscle
    DOI:  https://doi.org/10.1080/15376516.2026.2639053
  9. Sci Rep. 2026 Mar 14. pii: 9090. [Epub ahead of print]16(1):
    Potential gonadal-beneficial effect of sitagliptin against paclitaxel-induced testicular dysfunction via mediating PERK/CHOP/NLRP3/Sestrin2 signaling pathway.
    Kareman M El-Beheiry, Nagla A El-Shitany, Magda El-Sayed El-Sayad, Alaa E Elsisi.
      Paclitaxel (PTX) is broadly prescribed to treat various malignancies. However, it induces negative impacts on many organs, including testes. This study explored the beneficial role of sitagliptin (SIT) in PTX-provoked testicular damage and the underlying mechanisms. Rats were allocated into four groups: (I) control, (II) PTX, (III) PTX + SIT5, and (IV) PTX + SIT10. Histopathological and ultrastructural analyses were conducted along with sperm analysis. Immunohistochemical examinations of NOD-like receptor protein 3 (NLRP3), cleaved caspase-3, caspase-3, cytochrome c (Cyt.c), and interleukin-1 beta (IL-1β) were assessed. Serum testosterone and testicular 17β-hydroxy steroid dehydrogenase (17β-HSD), sestrin2, phosphorylated protein kinase R-like ER kinase (pPERK), and C/EBP homologous protein (CHOP) were determined. SIT induced a remarkable increase in sperm count, motility, and viability, with a pronounced decline in sperm abnormality compared to PTX group. SIT increased testosterone and 17β HSD levels. SIT elevates sestrin2, reduced glutathione (GSH), and catalase, and reduces malondialdehyde (MDA), reflecting its antioxidant action. SIT mitigates ER stress via diminishing pPERK and CHOP. SIT reduces NLRP3 and IL-1β levels, clarifying its anti-inflammatory action. SIT decreases cleaved caspase-3, caspase-3, and Cyt.c levels, verifying its anti-apoptotic features. Overall, SIT ameliorated PTX-provoked testicular dysfunction via mediating PERK/CHOP/NLRP3/Sestrin2 signaling pathway.
    Keywords:  NLRP3; PERK; Paclitaxel; Sestrin2; Sitagliptin; Testicular toxicity
    DOI:  https://doi.org/10.1038/s41598-026-40511-9
  10. iScience. 2026 Mar 20. 29(3): 115068
    Lipid overload triggers PERK-ALCAT1-mediated mitophagy failure in hepatocytes.
    Wenli Zhao, Yangguang Bao, Lei Liu, Yixin Gu, Xuran Liu, Óscar Monroig, Tingting Zhu, Peng Sun, Douglas R Tocher, Qicun Zhou, Min Jin.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), contact sites between the endoplasmic reticulum (ER) and mitochondria, are critical for calcium signaling and lipid metabolism. However, how MAMs contribute to mitochondrial dysfunction in lipid overload-induced fatty liver remains unclear. Here, using teleost fish as a model, we showed that high-fat diets promoted the aggregation of PERK and ALCAT1 at MAMs, causing mitochondrial calcium overload and membrane depolarization, and impairing PINK1/Parkin-dependent mitophagy. Acetylation of PERK at lysine 388 facilitated its binding to ALCAT1, while activation of SIRT1 by resveratrol induced site-specific deacetylation of PERK, disrupted PERK-ALCAT1 interaction, and restored mitophagy and mitochondrial integrity. These findings revealed a conserved SIRT1-PERK-ALCAT1 signaling axis linking ER stress to mitophagy failure and identified a potential nutritional intervention to alleviate lipid-induced hepatic injury. This mechanism is conserved across species and offers a basis for controlling metabolic dysfunction-associated steatotic liver disease (MASLD) in teleosts and potentially other vertebrate systems.
    Keywords:  Lipid; Metabolic flux analysis; Molecular network
    DOI:  https://doi.org/10.1016/j.isci.2026.115068
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