bims-unfpre 2025-06-29 papers

Issue of 2025–06–29
five papers selected by
Susan Logue, University of Manitoba

Nat Rev Cancer. 2025 Jun 24.

Endoplasmic reticulum stress responses in anticancer immunity.

Sung-Min Hwang, Shiun Chang, Paulo C Rodriguez, Juan R Cubillos-Ruiz.

The endoplasmic reticulum (ER) has a central role in processes essential for mounting effective and durable antitumour immunity; this includes regulating protein synthesis, folding, modification and trafficking in immune cells. However, the tumour microenvironment imposes hostile conditions that disrupt ER homeostasis in both malignant and infiltrating immune cells, leading to chronic activation of the unfolded protein response (UPR). Dysregulated ER stress responses have emerged as critical modulators of cancer progression and immune escape, influencing the initiation, development and maintenance of antitumour immunity. In this Review, we examine how tumour-induced ER stress reshapes the functional landscape of immune cells within the tumour microenvironment. We highlight recent discoveries demonstrating how ER stress curtails endogenous antitumour immunity and reduces the efficacy of immunotherapies. Furthermore, we underscore novel therapeutic strategies targeting ER stress sensors or UPR components to restore immune function and enhance cancer immunotherapy outcomes. Together, this provides a comprehensive overview of the interplay between ER stress responses and antitumour immunity, emphasizing the potential of UPR-targeted interventions to improve immune control of cancer.

DOI: https://doi.org/10.1038/s41568-025-00836-5

MedComm (2020). 2025 Jul;6(7): e70263

Endoplasmic Reticulum Stress in Cancer.

Ruixin Zhou, Wenlong Wang, Baizhao Li, Zhu Li, Juan Huang, Xinying Li.

Persistent and intense endoplasmic reticulum (ER) stress is widely acknowledged as a hallmark of tumorigenesis. To restore ER homeostasis, cells activate the unfolded protein response (UPR), which is aberrantly regulated in cancer cells. This review provides an in-depth analysis of the mechanisms through which the UPR facilitates tumor progression. The UPR is activated by ER stress sensors such as inositol-requiring enzyme 1 (IRE1α), protein kinase R-like ER-resident kinase (PERK), and activating transcription factor 6 (ATF6). These sensors regulate cancer cell proliferation, immune evasion, metastasis, and drug resistance. We summarize the crosstalk between the UPR and multiple signaling pathways, including mTOR, MAPK, and NF-κB, which collectively promote tumor growth and metastasis. Additionally, we discuss the role of the UPR in modulating the tumor microenvironment to support angiogenesis and immune evasion. We also provide an overview of pharmacological agents targeting specific UPR pathways, such as GRP78 inhibitors, IRE1α inhibitors, PERK inhibitors, and ATF6 inhibitors, with the aim of developing more effective cancer therapies. This comprehensive review highlights the potential of targeting the UPR as a novel strategy for cancer treatment and underscores the need for further research to elucidate the complex interactions between the UPR and cancer progression.

Keywords: endoplasmic reticulum (ER); metastasis; proliferation; tumor microenvironment (TME); unfolded protein response (UPR)

DOI: https://doi.org/10.1002/mco2.70263

J Virol. 2025 Jun 23. e0040525

Zika virus non-structural protein NS2A mediated endoplasmic reticulum stress through interacting with Sarco/endoplasmic reticulum Ca2+-ATPase 2.

Shan Wang, Shanshan Tang, Yuxin Zhou, Qifei An, Mengxing Du, Xiujuan Yang, Peng Zou, Li Tang, Yufeng Yu.

Zika virus (ZIKV) infection of neuronal cells leads to endoplasmic reticulum (ER) stress, which is one of the key causes of neuronal damage. However, how ZIKV mediates ER stress has not been fully understood. Here, we observed that ZIKV infection of astrocytes elevated Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) expression, increased intracellular Ca2+ concentration, and upregulated ER stress-related genes. SERCA2 was identified to regulate Ca2+ homeostasis and ER stress during ZIKV infection through both knockdown and overexpression of SERCA2 in astrocytes. Furthermore, ZIKV NS2A interacted with SERCA2 and increased the expression of SERCA2, disrupted Ca2+ homeostasis, and induced ER stress in astrocytes. After the knockdown of SERCA2 expression, Ca2+ homeostasis and ER stress were significantly mitigated in astrocytes expressing NS2A. Additionally, pTMS1-2 and pTMS4-5 of NS2A interacted with SERCA2 and regulated Ca2+ homeostasis and ER stress. ZIKV infection of the brains of BALB/c neonatal mice also elevated expression of SERCA2 and ER stress-related genes. Furthermore, SERCA2 expression facilitated ZIKV replication. These results suggested that ZIKV NS2A mediates ER stress through its interaction with SERCA2, providing new insights into the pathogenic mechanism of ZIKV and the development of anti-ZIKV therapies.
IMPORTANCE: Zika virus (ZIKV) infection induces intracellular Ca2+ imbalance and endoplasmic reticulum (ER) stress. However, the molecular mechanisms involved in it remain unknown. Here we reported, for the first time, that ZIKV infection increased the expression of Sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), which plays a crucial role in regulating Ca2+ homeostasis and ER stress. Furthermore, ZIKV NS2A was found to interact with SERCA2, contributing to the regulation of Ca2+ homeostasis and ER stress during ZIKV infection. And ZIKV NS2A pTMS1-pTMS2 and pTMS4-pTMS5 were the specific sites that interacted with SERCA2. These findings elucidate that the interaction between NS2A and SERCA2 is responsible for the regulation of the upstream signaling pathway of ER stress mediated by ZIKV infection. Additionally, the expression of SERCA2 promoted ZIKV proliferation, indicating that SERCA2 may serve as a potential target for anti-ZIKV therapies.

Keywords: ATP2A2; Ca2+ homeostasis; ER stress; NS2A; SERCA2; Zika virus

DOI: https://doi.org/10.1128/jvi.00405-25

Cancers (Basel). 2025 Jun 13. pii: 1972. [Epub ahead of print]17(12):

Activation of Unfolded Protein Response Pathway in Malignancies: Interplay with Extracellular Matrix and Targeting Perspectives.

Eleftherios N Athanasopoulos, Angeliki Natsiou, Maria Kyriazopoulou, Dimitra Manou, Achilleas D Theocharis, Vassiliki T Labropoulou.

Malignant cells exhibit elevated rates of protein synthesis and secretion to facilitate tumor growth, proliferation, and tumorigenesis. Upon malignant transformation, the endoplasmic reticulum (ER) experiences stress due to the accumulation of unfolded or misfolded proteins in the ER lumen, lack of nutrient availability and overall hostile tumor microenvironment conditions. The demand for regulated protein turnover and proteostasis reinstatement results in the activation of the unfolded protein response (UPR) pathway for cellular adaptation and survival. The UPR machinery utilizes the BiP chaperone and three ER-bound sensors, PERK, IRE1, and ATF6, to substantiate signal transduction and orchestrate gene expression associated with protein folding, degradation and recycling, inflammation, autophagy, and programmed cell death. The pleiotropic function of UPR emerges as a central mediator for tumor progression, especially in multiple myeloma and glioblastoma pathologies. Numerous studies have recently pointed out that communication of the extracellular matrix (ECM) with surrounding tumor cells dictates in part UPR activity and vice versa. In the context of this dynamic interplay, ER stress and UPR mechanisms have been proposed as potential targets to elicit novel and effective therapeutic approaches in clinical trials.

Keywords: endoplasmic reticulum stress; extracellular matrix; glioblastoma; multiple myeloma; signaling; unfolded protein response

DOI: https://doi.org/10.3390/cancers17121972

Nat Struct Mol Biol. 2025 Jun 25.

Structure of fungal tRNA ligase Trl1 with RNA reveals conserved substrate-binding principles.

Sandra Köhler, Jürgen Kopp, Satyabrata Maiti, Janusz M Bujnicki, Jirka Peschek.

RNA ligases play a vital role in RNA processing and maturation, including tRNA splicing, RNA repair and the unfolded protein response (UPR). In fungi and plants, the tripartite tRNA ligase Trl1 catalyzes the joining of TSEN-cleaved pre-tRNA exon halves. Trl1 also functions as ligase in the non-conventional HAC1 mRNA splicing during the UPR. The final ligation step is performed by the N-terminal adenylyltransferase domain (ligase; LIG). The spatial arrangement of the exon ends during the ligation reaction has remained elusive. Here we report the crystal structure of Chaetomium thermophilum Trl1-LIG in complex with a tRNA-derived substrate. Our structure represents a snapshot of the activated RNA intermediate and defines the conserved substrate-binding interface. The underlying enzyme-substrate interplay reveals a substrate-binding principle shared by adenylyltransferases. Moreover, we identify the determinants of RNA end specificity as well as the specific roles of Trl1-LIG's subdomains during ligase activation, substrate binding and phosphoryl transfer.

DOI: https://doi.org/10.1038/s41594-025-01589-3