bims-unfpre Biomed News
on Unfolded protein response
Issue of 2025–05–18
six papers selected by
Susan Logue, University of Manitoba



  1. Cell Commun Signal. 2025 May 13. 23(1): 223
      Cancer is influenced by the tumor microenvironment (TME), which includes factors such as pH, hypoxia, immune cells, and blood vessels. These factors affect cancer cell growth and behavior. The tumor microenvironment triggers adaptive responses such as endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and autophagy, posing a challenge to cancer treatment. The UPR aims to restore ER homeostasis by involving key regulators inositol-requiring enzyme-1(IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Additionally, ER-phagy, a selective form of autophagy, eliminates ER components under stress conditions. Understanding the interplay between hypoxia, ER stress, UPR, and autophagy in the tumor microenvironment is crucial for developing effective cancer therapies to overcome drug resistance. Targeting the components of the UPR and modulating ER-phagy could potentially improve the efficacy of existing cancer therapies. Future research should define the conditions under which ER stress responses and ER-phagy act as pro-survival versus pro-death mechanisms and develop precise methods to quantify ER-phagic flux in tumor cells.
    Keywords:  Autophagy; Drug resistance; ER Stress; ER-phagy; UPR
    DOI:  https://doi.org/10.1186/s12964-025-02232-w
  2. Cell Rep. 2025 May 13. pii: S2211-1247(25)00462-0. [Epub ahead of print]44(5): 115691
      Using in vitro models of lipotoxicity and islets from the db/db mouse model of type 2 diabetes (T2D), we show that endoplasmic reticulum (ER) stress impairs β cell function. This is unrelated to apoptosis or alterations in insulin content or proinsulin processing, despite expansion of the Golgi compartment. Instead, the constitutive secretory pathway and endocytic recycling are disrupted, as revealed by depletion of glycosylated proteins and syntaxins from the plasma membrane (PM) and accumulation of E-cadherin in the retromer. This involves the PERK arm of the unfolded protein response. Proteomics identified multiple PM proteins mislocalized by ER stress, notably axon-guidance and cell-adhesion proteins, and many with glycosylphosphatidylinositol linkages. A retromer chaperone attenuated defective insulin secretion from islets of both db/db and high-fat-fed mice. By identifying different endpoints and mechanisms, our results redefine the relevance of ER stress to β cell failure. They also implicate retromer chaperones as potential T2D therapeutics.
    Keywords:  CP: Metabolism; CP: Molecular biology; ER stress; Golgi complex; adherens junction; constitutive secretion; endocytosis; insulin secretion; lysosome; pancreatic β cell; plasma membrane; retromer; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.celrep.2025.115691
  3. Am J Cancer Res. 2025 ;15(4): 1829-1851
      The Endoplasmic reticulum (ER), an organelle present in various eukaryotic cells, is responsible for protein synthesis, modification, folding, and transport, as well as for the regulation of lipid metabolism and Ca2+ homeostasis. ER stress plays a pivotal role in the pathogenesis and therapeutic response of non-small cell lung cancer (NSCLC), significantly influencing cellular fate decisions through its unique sensing and regulatory mechanisms. This review aims to elucidate the key role of ER stress sensors and to explore how they mediate cell autophagy, apoptosis, and non-apoptotic modes of cell death in the context of drug-treated NSCLC. This investigation lays a solid foundation for optimizing future treatment strategies for NSCLC.
    Keywords:  Endoplasmic reticulum stress; autophagy; cell death; non-small cell lung cancer; unfolded protein response
    DOI:  https://doi.org/10.62347/RGRQ7608
  4. Cell Struct Funct. 2025 May 13.
      The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to maintain the homeostasis of the ER. The UPR consists of the IRE1, PERK and ATF6 pathways in vertebrates. Knockout of the IRE1 and PERK pathways causes defects in liver and pancreatic β cells, respectively, in mice, whereas knockout of the ATF6 pathway causes very early embryonic lethality in mice and medaka fish, a vertebrate model organism. We previously showed that ATF6 knockout in medaka causes a defect in the development of the notochord - the notochord becomes shorter - but that transient overexpression of the ER chaperone BiP via microinjection of BiP mRNA into one-cell stage embryos of these ATF6 knockout rescues this defect. Here, we microinjected mRNA encoding various ER chaperones and found that GRP94, calreticulin and calnexin also partially rescued this defect. Thus, BiP/GRP94 and calreticulin/calnexin greatly contribute to the development of the notochord by controlling the quality of collagens and N-glycosylated proteins (such as laminin and fibrillin), respectively, which have been confirmed necessary to the formation of the notochord in zebrafish genetics.Key words: endoplasmic reticulum, protein folding, molecular chaperone, collagen, glycoprotein.
    Keywords:  collagen; endoplasmic reticulum; glycoprotein; molecular chaperone; protein folding
    DOI:  https://doi.org/10.1247/csf.25009
  5. Cell Rep. 2025 May 09. pii: S2211-1247(25)00465-6. [Epub ahead of print]44(5): 115694
      The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity and microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent roles are less well understood, and its functions during fungal infection are still emerging. We demonstrate that Candida albicans activates macrophage IRE1α via C-type lectin receptor signaling independent of protein misfolding, suggesting non-canonical activation. IRE1α enhances macrophage fungicidal activity by promoting phagosome maturation, which is crucial for containing C. albicans hyphae. IRE1α facilitates early phagosomal calcium flux post-phagocytosis, which is required for phagolysosomal fusion. In macrophages lacking the IRE1α endoribonuclease domain, defective calcium flux correlates with fewer ER-early endosome contact sites, suggesting a homeostatic role for IRE1α-promoting membrane contact sites. Overall, our findings illustrate non-canonical IRE1α activation during infection and a function for IRE1α in supporting organelle contact sites to safeguard against rapidly growing microbes.
    Keywords:  CP: Immunology; CP: Microbiology; Candida albicans; IRE1α; calcium; fungal infection; innate immunity; phagosome
    DOI:  https://doi.org/10.1016/j.celrep.2025.115694
  6. Oncogene. 2025 May 14.
      Derlin-3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, its potential biomechanisms in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains to be elucidated. In the present study, we found that Derlin-3 was predominantly elevated in LUAD tissues, and could predict worse prognosis of LUAD patients. ScRNA-seq analysis indicated that Derlin-3 was mainly enriched in B lymphocytes in the TME, especially in plasma cells. Moreover, Derlin-3 may be involved in ER stress and IgG4 secretion in plasma cells by targeting Hrd1/p38/PRDM1 pathway. While the aberrant IgG4 production may be an essential driver of the polarization of macrophages towards the M2 phenotype. Additionally, downregulation of Derlin-3 could inhibit plasma cells infiltration and M2 macrophage polarization in vivo. Our results indicated that Derlin-3 could shape TME via ER stress to harness immune function, which might serve as a promising immunotherapeutic target in LUAD.
    DOI:  https://doi.org/10.1038/s41388-025-03435-8