bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–09–20
seven papers selected by
Susan Logue, University of Manitoba
  1. Necroptosis-related diseases are regulated by the unfolded protein response during endoplasmic reticulum stress.
  2. Cancer-associated fibroblasts drive immune resistance in MSS colorectal cancer via the FAIM2-CES1-ER stress pathway.
  3. The accessory protein ORF3a hijacks the CLCC1 chloride channel to disrupt ER homeostasis in betacoronavirus pathogenesis.
  4. Levocarnitine attenuates diabetic seminal vesicle fibrosis in association with improved lipid metabolism and reduced ER stress.
  5. Ashwin and FAM98 paralogs define nuclear and cytoplasmic RNA ligase complexes for tRNA biogenesis.
  6. Injury polarized CD4+ T cells orchestrate redox and unfolded protein responses to promote cardiac repair after myocardial infarction.
  7. Dynamic Prediction of Survival Outcomes in Multiple Myeloma.
  1. Genes Dis. 2027 Jan;14(1): 102060
    Necroptosis-related diseases are regulated by the unfolded protein response during endoplasmic reticulum stress.
    Tong Li, Tian Su, Sha Tang, Kun Cao, Pengbing Hua, Jingbiao Gao, Hongwang Cui, Tongmeng Jiang.
      In recent years, research has highlighted that necroptosis plays a significant role in various diseases, suggesting that studying the pathways of necroptosis may offer novel avenues for developing treatments for these conditions. The classical necroptosis pathway involves the activation and phosphorylation of RIPK1, RIPK3, and MLKL. Moreover, the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress is crucial in regulating necroptosis. ER stress impacts cell survival by activating the UPR, which subsequently influences downstream PERK, IRE1α, and ATF6 pathways. This paper will elucidate the signaling mechanisms within the classical necroptosis pathway and the three UPR pathways involved in ER stress. Additionally, this review will focus on the functional mechanisms of the UPR pathways in necroptosis and the latest research advancements on how these pathways regulate necroptosis and influence the progression of related diseases.
    Keywords:  ATF6; Endoplasmic reticulum (ER) stress; IRE1α; Necroptosis; PERK; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.gendis.2026.102060
  2. Mol Cell Biochem. 2026 Sep 15.
    Cancer-associated fibroblasts drive immune resistance in MSS colorectal cancer via the FAIM2-CES1-ER stress pathway.
    Ren Tang, Hongtao Wan, Menglan Zhong, Kangpeng Yan, Bin Xu, Jianyong Xiong.
      Microsatellite-stable (MSS) colorectal cancer (CRC) shows limited responsiveness to immune checkpoint inhibitors, often in the context of a fibrotic and immunosuppressive tumor microenvironment. Cancer-associated fibroblasts (CAFs) are central to extracellular matrix (ECM) remodeling, yet the underlying regulatory mechanisms remain unclear. Here, we identify Fas apoptotic inhibitory molecule 2 (FAIM2) as a stromal regulator that is downregulated in MSS CRC and associated with immune infiltration and patient prognosis. Single-cell RNA sequencing localizes FAIM2 predominantly to CAFs, where it inversely correlates with collagen production. Functional studies in L-929 cells and primary CAFs show that FAIM2 overexpression suppresses endoplasmic reticulum (ER) stress signaling and reduces collagen I and matrix metalloproteinase 2 (MMP2) expression; these effects are attenuated by the ER stress inducer Tunicamycin. Conversely, FAIM2 knockdown enhances ER stress and collagen synthesis, which are mitigated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Mechanistically, carboxylesterase 1 (CES1) is identified as a downstream effector negatively regulated by FAIM2, mediating ER stress and ECM remodeling. In vivo, FAIM2 overexpression restrains tumor growth, reduces collagen deposition, and promotes tertiary lymphoid structure (TLS) formation, whereas CES1 co-overexpression counteracts these effects. Together, these findings reveal a potential FAIM2-CES1-ER stress axis in CAFs associated with ECM remodeling and immune contexture in MSS CRC, providing a rationale for future studies exploring its therapeutic potential in immunotherapy.
    Keywords:  Cancer-associated fibroblasts; Endoplasmic reticulum stress; FAIM2; Immunotherapy resistance; Microsatellite-stable colorectal cancer; Tertiary lymphoid structures
    DOI:  https://doi.org/10.1007/s11010-026-05705-9
  3. Cell Discov. 2026 Sep 15. pii: 66. [Epub ahead of print]12(1):
    The accessory protein ORF3a hijacks the CLCC1 chloride channel to disrupt ER homeostasis in betacoronavirus pathogenesis.
    Liang Guo, Baoying Huang, Hanzhi Yu, Yi Xu, Lei Wei, Jijie Zheng, Yuanzhe Li, Di Wu, Peng Zhao, Changcheng Wu, Wenjie Tan, Yichang Jia.
      Beta-coronavirus infection disrupts endoplasmic reticulum (ER) homeostasis; however, the mechanisms by which viral proteins manipulate ER-resident factors remain unclear. Here, we report that the SARS-CoV-2 accessory protein ORF3a binds to the ER chloride channel CLCC1, thereby impairing ER ion homeostasis, activating the unfolded protein response, and inducing endomembrane remodeling. Using newly developed ratiometric reporters, we showed that this interaction exacerbated the basal levels of ER-phagy and nucleophagy. Importantly, CLCC1 counteracted ORF3a by sequestering it within the ER, attenuating its toxicity and suppressing viral replication, which established CLCC1 as a host restriction factor. We further elucidated a spatiotemporal mechanism: during early infection, ORF3a accumulates in the ER, co-assembles with CLCC1 into puncta, and disrupts ER homeostasis; at the later stage, ORF3a overload enables its escape from CLCC1-mediated ER retention and subsequent translocation to lysosomes, facilitating viral egress. This ER-centric function is conserved across diverse beta-coronaviruses, including SARS-CoV-1 and bat- or pangolin-derived strains, revealing a unified pathogenic strategy. Furthermore, in mouse brains, the ORF3a-CLCC1 axis recapitulates key neuropathological features, including ER stress, autophagic dysfunction, neuronal death, and neuroinflammation, providing a mechanistic link to COVID-19-associated neurological symptoms. Our findings identify CLCC1 as an essential host defense protein and establish a conceptual framework to guide future research on antiviral responses at the organelle level and related disease mechanisms.
    DOI:  https://doi.org/10.1038/s41421-026-00918-0
  4. iScience. 2026 Sep 18. 29(9): 116996
    Levocarnitine attenuates diabetic seminal vesicle fibrosis in association with improved lipid metabolism and reduced ER stress.
    Pengfei Liu, Yi Yu, Junjie Wu, Lei Wang, Fan Yao, Xueqin Chen, Kerong Wu, Xuejun Shang.
      Seminal vesicle integrity supports semen composition and sperm function, whereas type 2 diabetes mellitus can induce atrophy and fibrosis in this organ. Using a high-fat diet/streptozotocin-induced model in male mice and primary mouse seminal vesicle epithelial cells exposed to high glucose, we assessed fibrotic remodeling, lipid metabolism, PPARα/PGC-1α signaling, endoplasmic reticulum stress, and apoptosis through histological, biochemical, and lipidomic analyses. Diabetic seminal vesicles showed atrophy and fibrosis together with altered lipid profiles, free fatty acid accumulation, reduced PPARα/PGC-1α expression, and increased IRE1-associated stress and apoptosis. Levocarnitine attenuated these changes in vivo and reduced profibrotic responses in vitro. PPARα overexpression reproduced several protective effects, whereas IRE1 inhibition reduced stress-associated injury without restoring PPARα/PGC-1α signaling. These findings identify metabolic dysregulation and endoplasmic reticulum stress as associated features of diabetic seminal vesicle remodeling and support further evaluation of levocarnitine for diabetes-associated reproductive tract injury.
    Keywords:  endoplasmic reticulum stress; fibrosis; levocarnitine; lipid metabolism; seminal vesicle; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.isci.2026.116996
  5. Nat Commun. 2026 Sep 17. pii: 9882. [Epub ahead of print]17(1):
    Ashwin and FAM98 paralogs define nuclear and cytoplasmic RNA ligase complexes for tRNA biogenesis.
    Moritz Kleinwächter, Marius Moser, Nathan Raynaud, Moritz M Pfleiderer, Martin Jinek, Javier Martinez.
      The tRNA ligase complex (tRNA-LC) seals tRNA exon halves in the nucleus during pre-tRNA splicing and XBP1-mRNA exons in the cytoplasm as part of the unfolded protein response (UPR). This dual function requires the tRNA-LC to be either nuclear or cytoplasmic. Here, we reveal that Ashwin (ASW), the vertebrate-specific subunit of the tRNA-LC, serves as its nuclear import factor. ASW contains a dual nuclear localisation signal (NLS) which, upon disruption, leads to the retention of the tRNA-LC in the cytoplasm, impairing pre-tRNA splicing with the consequent accumulation of 5' tRNA fragments. We also show that the tRNA-LC exists in three forms, depending on which FAM98 paralog is bound, either FAM98A, FAM98B or FAM98C. ASW interacts exclusively with the FAM98B-containing complex, ensuring its nuclear localization for tRNA biogenesis. Attaching an NLS to RTCB, the catalytic and indispensable tRNA-LC subunit, rescues pre-tRNA splicing in cells depleted of ASW. We hypothesize that vertebrates evolved ASW to localize a sub-population of tRNA-LC to the nucleus, while using FAM98 paralogs to retain a fraction of RTCB in the cytoplasm to splice XBP1-mRNA during UPR.
    DOI:  https://doi.org/10.1038/s41467-026-77451-x
  6. Redox Biol. 2026 Sep 08. pii: S2213-2317(26)00382-4. [Epub ahead of print]97 104383
    Injury polarized CD4+ T cells orchestrate redox and unfolded protein responses to promote cardiac repair after myocardial infarction.
    Thomas Wc Knight, Fatma Saaoud, Ngefor Asangwe, Ying Shao, Iman Khan, Hajime Kubo, Mohsin Khan, Hong Wang, Raj Kishore, Xiaofeng Yang, Sadia Mohsin.
      Myocardial infarction (MI) initiates a wound-healing response where immune cells shape inflammation, tissue repair, and long-term remodeling. Although CD4+ T cells are increasingly recognized as contributors to post-MI healing, the transcriptional reprogramming defining their early pro-reparative functions remains incompletely resolved. Here, RNA sequencing of cardiac CD4+ T cells isolated 1 week after MI found that a substantial post-MI transcriptional fraction lay outside canonical cytokine-induced T helper subset polarization, including type 1 T helper cell (Th1), Th2, Th17, nature-occurring CD4+ regulatory T cell (nTreg), and peripherally induced Treg (iTreg) reference transcriptomic programs. Instead, this response was organized into a distinct CD4+ Th tissue injury-polarized (CD4+/TIP) transcriptomic module enriched for extracellular matrix organization, adhesion, vascular, and developmental programs, with a coordinated downregulated arm involving RNA metabolism, chromatin regulation, and protein catabolic processes. Within the CD4+/TIP population, MI induced and polarized at least 10 transcriptionally distinct CD4+ Th subsets at 1 week post-MI. Integration with curated transcription factors, epigenetic, reduction-oxidation (redox), and unfolded protein response (UPR) datasets identified a stress-adaptive architecture, in which regulatory subsets and the CD4+/TIP population shared redox attenuation features, while the CD4+/TIP state showed the strongest coupling to reparative tissue interaction programs, predominant Activating Transcription Factor 6 (ATF6)-aligned UPR structure, restrained proteostasis related outputs, and an innate-adjacent immune and secretome signature enriched for complement-associated, inflammatory recruitment, and extracellular communication genes. These findings identify a specific MI-associated CD4+ T-cell transcriptomic state during early MI inflammation and tissue repair. They establish a coordinated framework in which redox control, UPR, and tissue-injury-polarized CD4+ T-cell immune programs converge outside traditional Th and Treg lineages, offering new targets for CD4+ T-cell-mediated tissue repair after MI.
    Keywords:  CD4(+/TIP) T cells; Cardiac repair; Innate-like immunity; Myocardial infarction; Redox signaling; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.redox.2026.104383
  7. Cancers (Basel). 2026 Sep 04. pii: 2864. [Epub ahead of print]18(17):
    Dynamic Prediction of Survival Outcomes in Multiple Myeloma.
    Kelly Quek, Cindy H Lee, Yang Zhang, Barbara J McClure, Runzhe Chen, Hamish S Scott, Kate Vandyke, Andrew C W Zannettino, Chung Hoow Kok.
      Background: Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by marked clinical heterogeneity. Existing prognostic frameworks, including the International Staging System (ISS) and FISH-defined cytogenetic risk, are anchored at diagnosis and do not capture the evolutionary dynamics of disease or treatment response, leaving an unmet need for risk models that retain prognostic validity longitudinally. Methods: Using transcriptomic data from 762 CD138-selected MM plasma cells from newly diagnosed patient samples in the MMRF CoMMpass study (NCT01454297), we computed single-sample pathway activity scores for 469 curated cancer-relevant pathways (MSigDB Hallmark; Reactome) and learned a Bayesian causal network linking pathway activity to survival. The model was validated in five independent diagnostic cohorts (n = 1255) and in two independent treatment and relapsed/refractory cohorts (n = 319). Longitudinal risk tracking was additionally assessed in a 46-patient subset of the discovery cohort with serial pre- and post-treatment sampling. Results: The network identified five pathways associated with survival: unfolded protein response (UPR), FLT3 signaling through SRC family kinases, G2M DNA replication checkpoint, metabolism of selenium compound (SeMet), and nicotinate metabolism. The composite survival score stratified patients into high-risk (n = 76; 10%) and standard-risk groups with markedly divergent survival (median 1170 days vs. not reached; p < 0.0001). The score remained an independent prognostic factor after adjustment for age, sex, ISS stage, and KRAS, TP53, and UBR5 mutational status (HR 4.93; 95% CI 2.96-8.19; p < 0.001), and replicated across all five external diagnostic cohorts. Critically, the model retained prognostic discrimination in previously treated (GSE57317; p < 0.0001) and relapsed/refractory (GSE9782; p < 0.0001) settings, and patients transitioning from standard- to high-risk between serial samples exhibited significantly inferior survival compared to standard-risk patients. Conclusions: This pathway-based Bayesian network provides a reproducible, dynamically applicable risk model for MM that captures information complementary to ISS and FISH-defined cytogenetics. The framework supports longitudinal patient monitoring and may inform trial enrichment strategies and closer surveillance for high-risk subpopulations.
    Keywords:  Bayesian network; dynamic risk stratification; gene expression; molecular pathways; multiple myeloma; myeloma-specific survival; precision oncology; prognostication; transcriptomics
    DOI:  https://doi.org/10.3390/cancers18172864
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