Lei Haiyun, Fu Bao, Fu Xiaoyun
Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China. Corresponding author: Fu Xiaoyun, Email:
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2025 May;37(5):499-504. doi: 10.3760/cma.j.cn121430-20240729-00637.
Activating transcription factor 5 (ATF5) is a member of the activating transcription factor/cyclic adenosine monophosphate response element binding protein (ATF/CREB) family. As a stress-induced transcription factor, ATF5 plays a crucial role in cellular inflammatory stress responses. Under cellular inflammatory stress conditions, ATF5 maintains cell homeostasis and survival by regulating key genes in the mitochondrial unfolded protein response (UPR) and endoplasmic reticulum stress (ERS). As a key regulator in UPR, ATF5 senses mitochondrial stress and translocate to the nucleus to activate the transcription of UPR-related genes, thereby promoting mitochondrial function recovery. Meanwhile, in ERS, ATF5 maintains endoplasmic reticulum homeostasis by regulating the expression of genes related to protein folding, degradation, and apoptosis, determining cell survival or death. ATF5 plays a vital role in various cellular inflammatory stress responses. In infectious inflammation, ATF5 plays an important role in alleviating neuroinflammation and maintaining intestinal barrier function by regulating UPR. In inflammation related to degenerative diseases, ATF5 improves intervertebral disc degeneration and delays the progression of osteoarthritis by regulating UPR. In metabolic inflammation such as diabetes and obesity, ATF5 regulates UPR and ERS to maintain the function of pancreatic β-cells, controlling their survival or inducing apoptosis, thus influencing the progression of diabetes. ATF5 protects mitochondria in the kidneys, adipose tissue, and pancreas, slows the progression of diabetic nephropathy, and improves insulin sensitivity. Furthermore, in immune-related inflammation, ATF5 alleviates glomerulonephritis and promotes tissue repair by enhancing immune tolerance in dendritic cells. In summary, ATF5, as a key regulator in cellular inflammatory stress responses, maintains cell homeostasis through regulating UPR and ERS and determines cell fate. Its critical regulatory role in cellular inflammatory stress responses makes ATF5 a potential clinical therapeutic target. This article summarizes the structural features and translational regulatory mechanisms of ATF5, focusing on its role in cellular inflammatory stress responses, particularly its regulatory mechanisms in UPR and ERS, aiming to provide a theoretical basis for understanding ATF5's role in cell and organ protection and to offer new insights into the treatment of related inflammatory diseases.
激活转录因子5（ATF5）是激活转录因子/环磷酸腺苷反应元件结合蛋白（ATF/CREB）家族的成员。作为一种应激诱导的转录因子，ATF5在细胞炎症应激反应中起关键作用。在细胞炎症应激条件下，ATF5通过调节线粒体未折叠蛋白反应（UPR）和内质网应激（ERS）中的关键基因来维持细胞内稳态和细胞存活。作为UPR中的关键调节因子，ATF5感知线粒体应激并转位至细胞核以激活UPR相关基因的转录，从而促进线粒体功能恢复。同时，在ERS中，ATF5通过调节与蛋白质折叠、降解和凋亡相关的基因表达来维持内质网稳态，决定细胞的存活或死亡。ATF5在各种细胞炎症应激反应中起重要作用。在感染性炎症中，ATF5通过调节UPR在减轻神经炎症和维持肠道屏障功能方面发挥重要作用。在与退行性疾病相关的炎症中，ATF5通过调节UPR改善椎间盘退变并延缓骨关节炎的进展。在糖尿病和肥胖等代谢性炎症中，ATF5调节UPR和ERS以维持胰腺β细胞的功能，控制其存活或诱导凋亡，从而影响糖尿病的进展。ATF5保护肾脏、脂肪组织和胰腺中的线粒体，减缓糖尿病肾病的进展并提高胰岛素敏感性。此外，在免疫相关炎症中，ATF5通过增强树突状细胞的免疫耐受性来减轻肾小球肾炎并促进组织修复。总之，ATF5作为细胞炎症应激反应中的关键调节因子，通过调节UPR和ERS维持细胞内稳态并决定细胞命运。其在细胞炎症应激反应中的关键调节作用使ATF5成为潜在的临床治疗靶点。本文总结了ATF5的结构特征和翻译调控机制，重点阐述了其在细胞炎症应激反应中的作用，特别是其在UPR和ERS中的调控机制，旨在为理解ATF5在细胞和器官保护中的作用提供理论基础，并为相关炎症性疾病的治疗提供新的见解。
