bims-unfpre 2026-01-11 papers

Issue of 2026–01–11
five papers selected by
Susan Logue, University of Manitoba

Int J Mol Sci. 2026 Jan 02. pii: 474. [Epub ahead of print]27(1):

Necrotic Cells Alter IRE1α-XBP1 Signaling and Induce Transcriptional Changes in Glioblastoma.

Jiwoo Lim, Seulgi Lee, Ye-Seon Hong, Ji Ha Choi, Ala Jo, Jihee Lee Kang, Tae-Jin Song, Youn-Hee Choi.

Necrosis is a characteristic feature of glioblastoma multiforme (GBM) and is closely associated with tumor-associated inflammation and poor clinical outcomes. However, the molecular consequences of necrotic cell death on endoplasmic reticulum (ER) stress signaling in GBM cells remain unclear. In this study, we examined the effects of necrotic cells on the ER stress signaling and unfolded protein response (UPR) in human glioblastoma cell lines. Exposure to necrotic cells reduced IRE1α phosphorylation and increased unspliced XBP1 (XBP1u) accumulation, without affecting PERK or ATF6 pathways. These changes were accompanied by enhanced IκBα phosphorylation and impaired autophagic degradation. Treatment with ER stress inducers failed to reverse XBP1u accumulation, and reduced phosphorylation of PKAc was observed together with decreased IRE1α activation. Transcriptomic analysis and quantitative reverse transcription PCR (qRT-PCR) revealed that necrotic cell-induced XBP1u was associated with altered expression of XBP1-related genes, while XBP1 knockdown produced similar transcriptional changes and enhanced the effects of necrotic cell treatment. These findings suggest that necrotic cells impair canonical IRE1α-XBP1 signaling and induce transcriptional reprogramming in glioblastoma cells, which may contribute to tumor progression.

Keywords: IRE1α-XBP1 signaling; endoplasmic reticulum stress; glioblastoma; necrosis; unfolded protein response

DOI: https://doi.org/10.3390/ijms27010474

Signal Transduct Target Ther. 2026 Jan 05. 11(1): 7

The role of ER-associated degradation and ER-phagy in health and disease.

Young Joo Jeon, Ze'ev A Ronai.

The endoplasmic reticulum (ER) is a major cellular organelle for the synthesis and folding of secretory and transmembrane proteins, whose proper function underpins organellar homeostasis, proper tissue function, and organismal physiology. Protein quality control (PQC) systems at the ER include the unfolded protein response (UPR), ER-associated degradation (ERAD), and ER-phagy, which monitor ER homeostasis and contribute to protein refolding, sequestration, or degradation. ERAD prevents the accumulation of misfolded or orphan proteins that would otherwise be toxic. By controlling the degradation of these proteins, ERAD performs a core function in governing adaptation to proteotoxic stress. ERAD also regulates the abundance of folding-competent proteins as a means to fine-tune key physiological processes. Among its complex regulatory activities, ERAD controls cellular processes such as lipid homeostasis, calcium flux, and cell fate decisions, which are all required for the maintenance of organelle homeostasis. Highlighting its importance, dysregulation of ERAD often results in devastating diseases. Here, we discuss the molecular and mechanistic understanding of protein quality and quantity control by ERAD and its interface with ER-phagy, as well as other cellular stress programs. The implications of ERAD and its associated regulatory arms for cellular homeostasis, its effects on health and disease, and current therapeutic approaches are discussed.

DOI: https://doi.org/10.1038/s41392-025-02501-7

Hum Mol Genet. 2026 Jan 06. pii: ddaf199. [Epub ahead of print]

TULP1 missense mutations cause variable retinal phenotypes and activation of the endoplasmic reticulum unfolded protein response pathway.

Ke Jiang, Satyabrata Sinha, Vera L Bonilha, Minzhong Yu, Neal S Peachey, Stephanie A Hagstrom.

Mutations in TULP1 are associated with early-onset forms of inherited retinal degenerations (IRDs). Evidence from Tulp1-/- mice indicates that TULP1 plays a role in photoreceptor protein trafficking. Here we generated two novel knock-in mouse models, each expressing the ortholog to a human IRD-causing homozygous missense TULP1 mutation to: 1) better recapitulate IRD patients' gene dosage and spatiotemporal degeneration, 2) determine the pathological disease mechanism, and 3) evaluate mutations affecting different domains of the protein. The Tulp1F492L model carries a mutation affecting a conserved amino acid in the C-terminal tubby domain, whereas the Tulp1D89Y model carries the only homozygous mutation located outside the tubby domain. In both mutant retinas, TULP1F492L and TULP1D89Y protein levels and distribution were comparable to WT. Surprisingly, variable retinal phenotypes were observed in the two mutant lines. The Tulp1F492L model displayed rapid photoreceptor degeneration, rod and cone opsin mistrafficking, and abnormal shaped ribbon synapses, similar to Tulp1-/- mice. In contrast, these abnormalities were not seen in the Tulp1D89Y model; indeed, retinal morphology and function was preserved up to 12 months, although we noted less RPE pigmentation and dilated structures in the outer plexiform layer at this timepoint. Moreover, building on our prior in vitro results, we observed activation of the IRE1 branch of the endoplasmic reticulum (ER)-unfolded protein response (UPR) complex in Tulp1-/- and Tulp1F492L retinas, identifying ER stress as a key disease mechanism leading to photoreceptor death and as a potential therapeutic target in TULP1-associated forms of IRD.

Keywords: ERUPR; TULP proteins; inherited retinal disease; photoreceptor degeneration

DOI: https://doi.org/10.1093/hmg/ddaf199

Sci Rep. 2026 Jan 05.

Thapsigargin enhanced chemotherapeutic sensitivity of irinotecan in the inflammation-induced colorectal cancer model in mice.

Sukanya Baruah, Manuj Kumar Bharali, Nabila Akhtara, Jaydeep Kumar Nath, Sabana Sargam Rahman, Shehnaz Siddika Rasid, Mitali Baidya, Epham Mayum Mohd Samir Khan, Ritu Mishra.

The present study used an in-vivo inflammation-induced colorectal cancer (CRC) model to evaluate the additive effect of thapsigargin (TG) with the standard chemotherapy drug irinotecan (IRN). CRC was induced by AOM/DSS, and after 10th weeks, animals were treated with five weekly cycles of either IRN or TG or a combination of both drugs. All the animals were sacrificed after the 16th week, and the data were analysed. Coadministration of both IRN and TG substantially reduced both tumor numbers and occurrence of aberrant crypt foci (ACF) in the colon tissues as compared to only IRN/TG-treated animal groups. Further analyses revealed that IRN and TG together alleviated ultrastructural abnormalities of the colon with a recovered overall histoarchitecture, enhanced ER stress and mitochondrial dysfunction, reduction of PCNA positive cells indicating low rate of cellular proliferation, increased DNA fragmentation and apoptosis supported by higher intensity of γH2AX and cleaved caspase-3 immunohistochemistry. Gene expression analyses of key oncogenic biomarkers also suggest that the addition of TG with IRN is more effective in inhibiting carcinogenic transformation in the colon of AOM/DSS-treated mice. This study provides direct evidence of the superior therapeutic potential of a combination of both drugs compared to conventional monotherapy in the management of CRC.

Keywords: Apoptosis; Cellular proliferation; Colorectal cancer; Combination therapy; DNA fragmentation; Irinotecan; Thapsigargin

DOI: https://doi.org/10.1038/s41598-025-34567-2

Nat Commun. 2026 Jan 09.

Endothelial IRE1α promotes thrombospondin-1 mRNA decay and supports metabolic stress adaptation of pancreatic islets.

Vascular endothelial cells (ECs) play pivotal roles in maintaining metabolic tissue homeostasis, and EC dysfunction is associated with obesity and metabolic disorders. The mammalian ER stress sensor IRE1α kinase/RNase responds to metabolic cues, but it remains unclear whether endothelial IRE1α is implicated in controlling systemic metabolism. Here we show that genetic depletion of IRE1α in ECs leads to maladaptation of pancreatic islets under obesity-associated metabolic stress. We find that in high-fat diet-fed male mice, loss of IRE1α in ECs has no significant impact upon adiposity, but unexpectedly results in glucose intolerance with impaired insulin secretion, accompanied by blunted intra-islet angiogenesis and compensatory islet growth. Mechanistically, IRE1α RNase decays the mRNA encoding the endogenous anti-angiogenic factor thrombospondin-1 (THBS1/TSP1) in islet ECs. These findings thus uncover a critical role of the endothelial IRE1α suppression of THBS1 in governing the vascular support that enables the functional adaptation of islets to metabolic stress.

DOI: https://doi.org/10.1038/s41467-025-68276-1