Noncanonical UPR factor CREB3L2 drives immune evasion of triple-negative breast cancer through Hedgehog pathway modulation in T cells

Science Advances, Journal Year: 2025, Volume and Issue: 11(2)

Published: Jan. 10, 2025

The unfolded protein response (UPR) pathway is crucial for tumorigenesis, mainly by regulating cancer cell stress responses and survival. However, whether UPR factors facilitate cell-cell communication between cells immune to drive progression remains unclear. We found that adenosine 3′,5′-monophosphate element–binding 3–like 2 (CREB3L2), a noncanonical factor, overexpressed activated in triple-negative breast cancer, where its cleavage releases C-terminal fragment activates the Hedgehog neighboring CD8+ T cells. enhanced represses activation inhibits cytotoxic effects. Consequently, overexpression of CREB3L2 not only promotes tumor growth but also causes resistance checkpoint blockade (ICB). Inhibition impedes CREB3L2-overexpressed tumors sensitizes them ICB therapy. In summary, we identified previously unidentified mechanism which dictates cross-talk cells, providing important anticancer therapeutic opportunities.

Language: Английский

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Endoplasmic reticulum stress in the pathogenesis of chemotherapy‐induced mucositis: Physiological mechanisms and therapeutic implications

Acta Physiologica, Journal Year: 2024, Volume and Issue: 240(8)

Published: June 14, 2024

Chemotherapy is a common and effective treatment for cancer, but these drugs are also associated with significant side effects affecting patients' well-being. One such debilitating effect mucositis, characterized by inflammation, ulcerations, altered physiological functions of the gastrointestinal (GI) tract's mucosal lining. Understanding mechanisms chemotherapy-induced intestinal mucositis (CIM) crucial developing preventive measures supportive care. Chemotherapeutics not only target cancer cells rapidly dividing in GI tract. These disrupt endoplasmic reticulum (ER) homeostasis, leading to ER-stress activation unfolded protein response (UPR) various epithelial cell types. The UPR triggers signaling pathways that exacerbate tissue inflammation damage, influence differentiation fate cells, compromise integrity barrier. factors contribute significantly development progression. In this review, we aim give an in-depth overview role its impact on function. This will provide valuable insights into underlying highlighting potential therapeutic interventions could improve treatment-outcomes quality life patients.

Language: Английский

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Insights into the Activation of Unfolded Protein Response Mechanism during Coronavirus Infection

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(5), P. 4286 - 4308

Published: May 5, 2024

Coronaviruses represent a significant class of viruses that affect both animals and humans. Their replication cycle is strongly associated with the endoplasmic reticulum (ER), which, upon virus invasion, triggers ER stress responses. The activation unfolded protein response (UPR) within infected cells performed from three transmembrane receptors, IRE1, PERK, ATF6, results in reduction production, boost ER’s ability to fold proteins properly, initiation ER-associated degradation (ERAD) remove misfolded or proteins. However, cases prolonged severe stress, UPR can also instigate apoptotic cell death inflammation. Herein, we discuss ER-triggered host responses after coronavirus infection, as well pharmaceutical targeting potential antiviral strategy.

Language: Английский

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ATF6 enables pathogen infection in ticks by inducing stomatin and altering cholesterol dynamics

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

How tick-borne pathogens interact with their hosts has been primarily studied in vertebrates where disease is observed. Comparatively less known about pathogen interactions within the tick. Here, we report that Ixodes scapularis ticks infected either Anaplasma phagocytophilum (causative agent of anaplasmosis) or Borrelia burgdorferi Lyme disease) show activation ATF6 branch unfolded protein response (UPR). Disabling functionally restricts survival ticks. When stimulated, functions as a transcription factor, but least understood out three UPR pathways. To interrogate transcriptional network, developed custom R script to query tick promoter sequences. This revealed stomatin potential gene target, which roles lipid homeostasis and vesical transport. was experimentally validated bona fide ATF6-regulated through luciferase reporter assays, pharmacological activators, RNAi repression. Silencing decreased A. colonization disrupted cholesterol dynamics cells. Furthermore, blocking restricted availability bacterium, thereby inhibiting growth survival. Taken together, have identified pathway novel contributor vector competence Stomatin-regulated homeostasis. Moreover, our custom, web-based factor binding site search tool "ArthroQuest" nature unique blood-feeding arthropods. Collectively, these findings highlight importance studying fundamental processes non-model organisms. Host-pathogen for like Anaplasmosis) mammalian hosts. Herein, find activate cellular stress receptor, ATF6, Upon activation, cleaved cytosolic portion translocates nucleus function coordinates expression networks. Using regulome, an target supports by facilitating bacterium. found Given hijacking common among arthropod-borne microbes, ATF6-mediated induction may be mechanism exploited many vector-pathogen relationships persistence transmissible microbes. this study highlights molecular networks

Language: Английский

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A deafness-blindness syndrome results from ATF6-based disruption of the unfolded protein response

Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: 135(3)

Published: Feb. 2, 2025

Sensorineural hearing loss (SNHL) is the most prevalent form of permanent impairment, arising from factors such as aging, exposure to loud noise, disease, ototoxic medications, and genetic mutations. Despite extensive research, effective treatments or cures for SNHL remain elusive. In this issue JCI, Lee et al. reveal a link between mutations in ATF6 patients with achromatopsia. The study also shows that Atf6-deficient (Atf6-/-) mice exhibit disorganized stereocilia age-related outer hair cells. Additionally, researchers show Atf6 critical cochlear cell function. Mice lacking expression experienced ER stress, which ultimately led SNHL. Collectively, these findings enhance our understanding emerging role protein homeostasis stress pathogenesis

Language: Английский

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PERK-Olating Through Cancer: A Brew of Cellular Decisions

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 248 - 248

Published: Feb. 8, 2025

The type I protein kinase PERK is an endoplasmic reticulum (ER) transmembrane that plays a multifaceted role in cancer development and progression, influencing tumor growth, metastasis, cellular stress responses. activation of represents one the three signaling pathways induced during unfolded response (UPR), which triggered, particular, cells constitutively experience various intracellular extracellular stresses impair folding within ER. can lead to both pro-survival proapoptotic outcomes, depending on context extent ER stress. It helps reprogramming gene expression cells, thereby ensuring survival face oncogenic stress, such as replicative DNA damage, also microenvironmental challenges, including hypoxia, angiogenesis, metastasis. Consequently, contributes initiation, transformation, adaptation microenvironment, chemoresistance. However, sustained cell proliferation promote apoptotic death by interconnected processes, mitochondrial dysfunction, translational inhibition, accumulation stresses, specific induction multifunctional factors, CHOP. dual promoting progression suppression makes it complex target for therapeutic interventions. A comprehensive understanding intricacies pathway their impact essential effective strategies, particularly diseases like cancer, where deregulated most, if not all, solid liquid tumors. This article provides overview knowledge acquired from study animal models lines cultured vitro PERK’s functions thus highlighting potential new avenues could this protein.

Language: Английский

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Irisin: muscle’s novel player in endoplasmic reticulum stress and disease

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Language: Английский

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Embelin improves alcoholic steatohepatitis in alcohol-associated liver disease via ATF6-mediated P2X7r-NLRP3 signaling pathway

Phytomedicine, Journal Year: 2025, Volume and Issue: unknown, P. 156638 - 156638

Published: March 1, 2025

Language: Английский

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Corticosterone effects induced by stress and immunity and inflammation: mechanisms of communication

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 16

Published: March 20, 2025

The body instinctively responds to external stimuli by increasing energy metabolism and initiating immune responses upon receiving stress signals. Corticosterone (CORT), a glucocorticoid (GC) that regulates secretion along the hypothalamic-pituitary-adrenal (HPA) axis, mediates neurotransmission humoral regulation. Due widespread expression of receptors (GR), effects CORT are almost ubiquitous in various tissue cells. Therefore, on one hand, is molecular signal activates body’s system during other due chemical properties GCs, anti-inflammatory act as stabilizers control response stress. Inflammation manifestation activation. plays dual roles this process both promoting inflammation exerting As hormone, levels fluctuate with degree duration stress, determining its changes it induces. essential for resist diseases maintain homeostasis, imbalance being key factor development diseases. understanding role mechanisms action immunity crucial. This review addresses important issue summarizes interactions between system.

Language: Английский

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Indole-3-acetic acid and chenodeoxycholic acid attenuate TLR4/NF-κB signaling and endoplasmic reticulum stress in valproic acid-induced neurotoxicity

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 24, 2025

Valproic acid (VA) is a commonly prescribed medication for epilepsy and other neurological conditions. Although effective, VA use can lead to neurotoxicity, especially with chronic use. This study aimed investigate the potential neuroprotective properties of indole-3-acetic (IAA) chenodeoxycholic (CDCA) in an animal model VA-induced brain injury. Rats received intraperitoneal injections at dose 500 mg/kg/day 3 weeks. Concurrently, they were orally treated IAA (40 mg/kg/day) and/or CDCA (90 mg/kg/day). The results showed significantly increased oxidative stress inflammation markers VA-exposed group indicated by reduced levels glutathione (GSH, P < 0.0001) superoxide dismutase (SOD, 0.01) elevated inflammatory cytokines Interleukin-6 (IL-6, tumor necrosis factor-alpha (TNFα, 0.01). also induced nuclear factor kappa B (NF-κB, 0.01), toll-like receptor 4 (TLR4, 0.05), endoplasmic reticulum (ER) markers, as evidenced immunoreactivity GRP78 (glucose-regulated protein 78, 0.0001), transcription 6 (ATF-6, 0.05) CHOP (C/EBP homologous protein, 0.0001). Treatment or attenuated variable extent, improving oxidative, inflammatory, ER markers. demonstrates that exert protective effects against neurotoxicity mitigating stress, inflammation, stress. Further investigations are recommended validate these findings models.

Language: Английский

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