bims-unfpre 2025-01-26 papers

Issue of 2025–01–26
four papers selected by
Susan Logue, University of Manitoba

Front Immunol. 2024 ;15 1515715

Unfolded protein responses in T cell immunity.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are integral to T cell biology, influencing immune responses and associated diseases. This review explores the interplay between the UPR and T cell immunity, highlighting the role of these cellular processes in T cell activation, differentiation, and function. The UPR, mediated by IRE1, PERK, and ATF6, is crucial for maintaining ER homeostasis and supporting T cell survival under stress. However, the precise mechanisms by which ER stress and the UPR regulate T cell-mediated immunity remain incompletely understood. Emerging evidence suggests that the UPR may be a potential therapeutic target for diseases characterized by T cell dysfunction, such as autoimmune disorders and cancer. Further research is needed to elucidate the complex interactions between ER stress, the UPR, and T cell immunity to develop novel therapeutic strategies for T cell-associated diseases.

Keywords: T cell activation; T cell differentiation; endoplasmic reticulum stress; immune regulation; unfolded protein response

DOI: https://doi.org/10.3389/fimmu.2024.1515715

Pharmacol Ther. 2025 Jan 16. pii: S0163-7258(25)00010-5. [Epub ahead of print] 108798

Unfolded protein responses: Dynamic machinery in wound healing.

Morgan Minjares, Pattaraporn Thepsuwan, Kezhong Zhang, Jie-Mei Wang.

Skin wound healing is a dynamic process consisting of multiple cellular and molecular events that must be tightly coordinated to repair the injured tissue efficiently. The healing pace is decided by the type of injuries, the depth and size of the wounds, and whether wound infections occur. However, aging, comorbidities, genetic factors, hormones, and nutrition also impact healing outcomes. During wound healing, cells undergo robust processes of synthesizing new proteins and degrading multifunctional proteins. This imposes an increasing burden on the endoplasmic reticulum (ER), causing ER stress. Unfolded protein response (UPR) represents a collection of highly conserved stress signaling pathways originated from the ER to maintain protein homeostasis and modulate cell physiology. UPR is known to be beneficial for tissue healing. However, when excessive ER stress exceeds ER's folding potential, UPR pathways trigger cell apoptosis, interrupting tissue regeneration. Understanding how UPR pathways modulate the skin's response to injuries is critical for new interventions toward the control of acute and chronic wounds. Herein, in this review, we focus on the participation of the canonical and noncanonical UPR pathways during different stages of wound healing, summarize the available evidence demonstrating UPR's unique position in balancing homeostasis and pathophysiology of healing tissues, and highlight the understudied areas where therapeutic opportunities may arise.

Keywords: Endoplasmic reticulum; Gene therapy; Unfolded protein response; Wound healing

DOI: https://doi.org/10.1016/j.pharmthera.2025.108798

bioRxiv. 2025 Jan 09. pii: 2025.01.08.632070. [Epub ahead of print]

SLFN11-mediated tRNA regulation induces cell death by disrupting proteostasis in response to DNA-damaging agents.

Yuki Iimori, Teppei Morita, Takeshi Masuda, Shojiro Kitajima, Nobuaki Kono, Shun Kageyama, Josephine Galipon, Atsuo T Sasaki, Akio Kanai.

DNA-damaging agents (DDAs) have long been used in cancer therapy. However, the precise mechanisms by which DDAs induce cell death are not fully understood and drug resistance remains a major clinical challenge. Schlafen 11 (SLFN11) was identified as the gene most strongly correlated with the sensitivity to DDAs based on mRNA expression levels. SLFN11 sensitizes cancer cells to DDAs by cleaving and downregulating tRNA Leu (TAA). Elucidating the detailed mechanism by which SLFN11 induces cell death is expected to provide insights into overcoming drug resistance. Here, we show that, upon administration of DDAs, SLFN11 cleaves tRNA Leu (TAA), leading to ER stress and subsequent cell death regulated by inositol-requiring enzyme 1 alpha (IRE1α). These responses were significantly alleviated by SLFN11 knockout or transfection of tRNA Leu (TAA). Our proteomic analysis suggests that tRNA Leu (TAA) influences proteins essential for maintaining proteostasis, especially those involved in ubiquitin-dependent proteolysis. Additionally, we identified the cleavage sites of tRNA Leu (TAA) generated by SLFN11 in cells, and revealed that tRNA fragments contribute to ER stress and cell death. These findings suggest that SLFN11 plays a crucial role in proteostasis by regulating tRNAs, and thus determines cell fate under DDA treatment. Consequently, targeting SLFN11-mediated tRNA regulation could offer a novel approach to improve cancer therapy.
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DOI: https://doi.org/10.1101/2025.01.08.632070

JCI Insight. 2025 Jan 23. pii: e183959. [Epub ahead of print]10(2):

Inhibition of vascular smooth muscle cell PERK/ATF4 ER stress signaling protects against abdominal aortic aneurysms.

Brennan Callow, Xiaobing He, Nicholas Juriga, Kevin D Mangum, Amrita Joshi, Xianying Xing, Andrea Obi, Abhijnan Chattopadhyay, Dianna M Milewicz, Mary X O'Riordan, Johann Gudjonsson, Katherine Gallagher, Frank M Davis.

Abdominal aortic aneurysms (AAA) are a life-threatening cardiovascular disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by vascular smooth muscle cell (VSMC) dysfunction and apoptosis, for which the mechanisms regulating loss of VSMCs within the aortic wall remain poorly defined. Using single-cell RNA-Seq of human AAA tissues, we identified increased activation of the endoplasmic reticulum stress response pathway, PERK/eIF2α/ATF4, in aortic VSMCs resulting in upregulation of an apoptotic cellular response. Mechanistically, we reported that aberrant TNF-α activity within the aortic wall induces VSMC ATF4 activation through the PERK endoplasmic reticulum stress response, resulting in progressive apoptosis. In vivo targeted inhibition of the PERK pathway, with VSMC-specific genetic depletion (Eif2ak3fl/fl Myh11-CreERT2) or pharmacological inhibition in the elastase and angiotensin II-induced AAA model preserved VSMC function, decreased elastin fragmentation, attenuated VSMC apoptosis, and markedly reduced AAA expansion. Together, our findings suggest that cell-specific pharmacologic therapy targeting the PERK/eIF2α/ATF4 pathway in VSMCs may be an effective intervention to prevent AAA expansion.

Keywords: Cardiovascular disease; Cell stress; Surgery; Vascular biology

DOI: https://doi.org/10.1172/jci.insight.183959