Bidwell Joseph P, Robling Alexander G, Wek Ronald C
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, Indiana, USA; Indiana Center for Musculoskeletal Health, IUSM, Indianapolis, Indiana, USA.
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, Indiana, USA; Indiana Center for Musculoskeletal Health, IUSM, Indianapolis, Indiana, USA; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA.
J Biol Chem. 2025 Aug 5;301(9):110562. doi: 10.1016/j.jbc.2025.110562.
Defective secretory cell function underlies many diseases, and recent therapeutic strategies have focused on enhancing protein synthesis and delivery by targeting the secretory machinery of mature cells. However, mature differentiated cells appear to have intrinsic limits to their secretory capacity. In this review, we propose new strategies for engineering these cells to overcome these limits on secretion. The integrated stress response (ISR) and the related unfolded protein response (UPR) are stress adaptation systems that modulate transcriptional and translational programs of gene expression. These programs drive remodeling of cellular architecture to boost protein production and trafficking but also play critical roles in the differentiation of secretory cells. This dual function suggests that the limits of the secretory capacity of mature cells are pre-programmed during development. A potentially more effective therapeutic approach to expand protein secretion may lie in reprogramming the secretory capacity early in differentiation. Two additional transcriptional programs work in concert with the ISR and UPR to shape differentiated cell identities, their secretory outputs, and production capacity. The first involves lineage-determining transcription factors that define both cell type and secretory products. The second involves "scaling factors" that set the magnitude of the cell's protein synthesis and secretion capacity. We explore the mechanisms by which these three programs-lineage specification, scaling, and stress adaptation-interact to define and potentially enhance secretory capacity. We will illustrate this integrated model across several secretory cell types, including pancreatic, plasma, pituitary, and bone secretory cells, with a focus on applications to enhance therapeutic outcomes in osteoporosis.
分泌细胞功能缺陷是许多疾病的基础，近期的治疗策略集中在通过靶向成熟细胞的分泌机制来增强蛋白质合成和转运。然而，成熟分化细胞的分泌能力似乎存在内在限制。在本综述中，我们提出了改造这些细胞以克服这些分泌限制的新策略。整合应激反应（ISR）和相关的未折叠蛋白反应（UPR）是调节基因表达转录和翻译程序的应激适应系统。这些程序驱动细胞结构重塑以促进蛋白质产生和运输，但在分泌细胞分化中也起着关键作用。这种双重功能表明成熟细胞分泌能力的限制在发育过程中就已预先设定。一种可能更有效的扩大蛋白质分泌的治疗方法可能在于在分化早期对分泌能力进行重编程。另外两个转录程序与ISR和UPR协同作用，塑造分化细胞的特性、它们的分泌产物和生产能力。第一个涉及决定细胞谱系的转录因子，其定义了细胞类型和分泌产物。第二个涉及“缩放因子”，其设定了细胞蛋白质合成和分泌能力的大小。我们探讨这三个程序——细胞谱系特化、缩放和应激适应——相互作用以定义并潜在增强分泌能力的机制。我们将在几种分泌细胞类型中阐述这个整合模型，包括胰腺、血浆、垂体和骨分泌细胞，重点是在改善骨质疏松症治疗效果方面的应用。
