bims-unfpre 2025-02-23 papers

Issue of 2025–02–23
six papers selected by
Susan Logue, University of Manitoba

Virology. 2025 Feb 06. pii: S0042-6822(25)00060-1. [Epub ahead of print]604 110448

ATF6-mediated mild ER stress inhibits HBV transcription and replication, which is dependent on mTOR activation.

Lin Lu, Ying Feng, Yucai Geng, Zhixiang Liu, Yan Wu, Chen Cai, Ji Zhang, Xingda Huang, Tongchun Xue, Bo Gao.

Chronic hepatitis B (CHB) remains a serious global health problem. In our previous investigation, HBV was found to activate a mild ER stress, which facilitated the establishment of persistent HBV infection. However, the role of ER stress manipulation in HBV replication and its underlying mechanisms remain still unclear. Our data showed that mild ER stress inhibited HBV transcription and replication, while severe ER stress enhanced them. Mechanistically, in contrary to the effect on HBV replication, mild ER stress activated whereas severe ER stress inhibited mTOR signaling in HBV-infected cells. Further, mTOR signaling was revealed to be critical for mild ER stress-mediated HBV inhibition. Furthermore, ATF6 but not PERK or IRE1α was found to be involved in mild ER stress-mediated mTOR and the following HBV inhibition. Moreover, ATF6, per se, could inhibit HBV transcription and replication via activating mTOR signaling. Together, ATF6-mediated mild ER stress inhibited HBV transcription and replication through mTOR activation, which might present as an important therapeutic target for CHB patients.

Keywords: ATF6; HBV replication; HBV transcription; Mild ER stress; mTOR signaling

DOI: https://doi.org/10.1016/j.virol.2025.110448

Cell Stress Chaperones. 2025 Feb 19. pii: S1355-8145(25)00010-0. [Epub ahead of print]

The Protective Role of the IRE1α/XBP1 Signaling Cascade in Autophagy During Ischemic Stress and Acute Kidney Injury.

Ting Liu, Lu Li, Meixia Meng, Ming Gao, Jinhua Zhang, Yuan Zhang, Yukun Gan, Yangjie Dang, Limin Liu.

Acute kidney injury (AKI) is a common and serious complication resulting from ischemia and hypoxia, leading to significant morbidity and mortality. Autophagy, a cellular process for degrading damaged components, plays a crucial role in kidney protection. The unfolded protein response (UPR) pathway, particularly the IRE1α/XBP1 signaling cascade, is implicated in regulating autophagy during renal stress. To elucidate the role of the IRE1α/XBP1 pathway in autophagy during hypoxia/reoxygenation (H/R) and ischemia/reperfusion (I/R) injury, renal tubular epithelial cells (TECs) were subjected to H/R conditions, and I/R injury was induced in mice. The expression of autophagy-related and ER stress markers (IRE1α, XBP1, GRP78, Beclin1, LC3I/II, and P62) was assessed using immunoblotting and immunofluorescence. Additionally, the impacts of IRE1α overexpression and pharmacological agents, IXA6 (IRE1α agonist) and STF083010 (IRE1α inhibitor), were evaluated on autophagy regulation. H/R injury significantly increased mitochondrial damage and the formation of autophagic vesicles in TECs. Key markers of autophagy were elevated in response to H/R and I/R injury, with activation of the IRE1α/XBP1 pathway enhancing autophagic processes. IXA6 treatment improved renal function and reduced injury in I/R models, while STF083010 exacerbated kidney damage. The IRE1α/XBP1 pathway is a critical regulator of autophagy in renal TECs during ischemic stress, suggesting that pharmacological modulation of this pathway may offer therapeutic avenues for preventing or mitigating AKI. Enhanced understanding of these mechanisms may lead to novel strategies for kidney disease management.

Keywords: Autophagy; Endoplasmic reticulum stress; Ischemia-reperfusion; XBP1s; chronic kidney disease

DOI: https://doi.org/10.1016/j.cstres.2025.02.004

Brain. 2025 Feb 21. pii: awae407. [Epub ahead of print]

Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B.

Thierry Touvier, Francesca A Veneri, Anke Claessens, Cinzia Ferri, Rosa Mastrangelo, Noémie Sorgiati, Francesca Bianchi, Serena Valenzano, Ubaldo Del Carro, Cristina Rivellini, Phu Duong, Michael E Shy, Jeffery W Kelly, John Svaren, R Luke Wiseman, Maurizio D'Antonio.

Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.

Keywords: Charcot-Marie-Tooth; Schwann cell; XBP1; demyelinating neuropathy; proteostasis; unfolded protein response

DOI: https://doi.org/10.1093/brain/awae407

Cell Death Dis. 2025 Feb 15. 16(1): 101

The integrated stress response engages a cell-autonomous, ligand-independent, DR5-driven apoptosis switch.

Francesca Zappa, Nerea L Muniozguren, Julia E Conrad, Diego Acosta-Alvear.

The integrated stress response (ISR) is a fundamental signaling network that leverages the cell's biosynthetic capacity against different stresses to restore homeostasis. However, when homeostasis is unattainable, the ISR switches to drive cell death and eliminate irreparably damaged cells. Previous work has shown that persistent activity of the ISR kinase PERK during unyielding endoplasmic reticulum (ER) stress induces apoptosis downstream of death receptor 5 (DR5) [1]. ER stress provides activating signals that engage the ectodomain (ED) of DR5 to drive its unconventional activation in the Golgi apparatus [1, 2]. Here, using chemical genetics to uncouple stress sensing from ISR activation, we found that DR5 signaling from the Golgi apparatus is integral to the ISR and not specific to ER stress. Furthermore, we show that DR5 activation can be driven solely by increased expression and does not require its ED. These findings indicate that a general ISR kill switch eliminates irreversibly injured cells.

DOI: https://doi.org/10.1038/s41419-025-07403-8

Cell Death Dis. 2025 Feb 19. 16(1): 117

Sephin1 suppresses ER stress-induced cell death by inhibiting the formation of PP2A holoenzyme.

Satoshi Gojo, Daisuke Kami, Arata Sano, Fumiya Teruyama, Takehiro Ogata, Satoaki Matoba.

Sephin1 was discovered as a protein phosphatase inhibitor, and its efficacy against neurodegenerative diseases has been confirmed. There are conflicting reports on whether inhibition of eIF2α dephosphorylation by PP1 holoenzyme with the protein phosphatase 1 regulatory subunit 15 A is the mechanism of action of Sephin1. In the present study, we found that Sephin1 significantly suppressed renal tubular cell death in an animal model of ER stress administered with tunicamycin. CHOP, which plays a central role in the ER stress-induced cell death pathway, requires nuclear translocation to act as a transcription factor to increase the expression of cell death-related genes. Sephin1 markedly suppressed this nuclear translocation of CHOP. To elucidate the molecular mechanism underlying the cell death suppressive effect of Sephin1, we used human renal tubular epithelial cells under ER stress with tunicamycin. Sephin1 reduced intracellular CHOP levels by promoting CHOP phosphorylation at Ser30, which led to protein degradation in UPS. Phosphorylated CHOP is generated by Thr172-phosphorylated activated AMPK, and Sephin1 increased phosphorylated AMPK. Phosphorylated AMPK is inactivated by PP2A through dephosphorylation of its Thr172, and Sephin1 inhibits the formation of the PP2A holoenzyme with the PP2A subunit B isoform delta. These results indicate that inhibition of PP2A holoenzyme formation is the molecular target of Sephin1 in this experimental system.

DOI: https://doi.org/10.1038/s41419-025-07450-1

Plant Commun. 2025 Feb 13. pii: S2590-3462(25)00046-X. [Epub ahead of print] 101284

The core morning clock component CCA1 positively regulates the expression of UPR target genes for ER stress recovery.

Gyeongik Ahn, In Jung Jung, Gyeong-Im Shin, Song Yi Jeong, Myung Geun Ji, Jin-Sung Huh, Ji-Won Hwang, Jeongsik Kim, Joon-Yung Cha, Sang Yeol Lee, Min Gab Kim, Woe-Yeon Kim.

The endoplasmic reticulum (ER) is a cellular organelle responsible for protein synthesis and folding. When the protein folding capacity is exceeded, unfolded or misfolded proteins accumulate, causing ER stress and triggering the unfolded protein response (UPR) to restore ER proteostasis. Although UPR genes in plants are expressed in a diel cycle, the mechanisms by which the circadian clock regulates these genes are not well understood. Here, we demonstrate that ER stress sensitivity in root growth exhibits time-of-day phases and that the circadian clock regulates the expression of UPR target genes during ER stress. Notably, mutations in the core morning clock component CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) impair ER stress recovery. CCA1 forms a complex with the UPR modulator bZIP28 and acts as upstream regulator in ER stress recovery. Upon ER stress, CCA1 is stabilized and associates with bZIP28 at the ER stress response element of the BiP3 promoter, enhancing the ER stress response. Thus, CCA1 coordinates a time-dependent adaptive response to ER stress with bZIP28 to maintain ER proteostasis. Our results suggest that the circadian clock primes the timing and levels of ER chaperone expression to enhance ER stress tolerance.

Keywords: CCA1; Circadian clock; ER chaperone; ER stress; bZIP28

DOI: https://doi.org/10.1016/j.xplc.2025.101284