Backe Sarah J, Heritz Jennifer A, Mollapour Mehdi
Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Cancer Center, SUNY Upstate Medical University, Syracuse, NY, 13210.
Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Cancer Center, SUNY Upstate Medical University, Syracuse, NY, 13210.
Cell Stress Chaperones. 2025 Sep 20;30(6):100118. doi: 10.1016/j.cstres.2025.100118.
Molecular chaperones maintain proteostasis by assisting protein folding, stability, and activity. Heat shock protein 70 (Hsp70) and Hsp90 (Hsp90) are ATP-dependent chaperones essential for protein quality control, signaling, and stress adaptation. Their activities are controlled not only by co-chaperones, but also by dynamic post-translational modifications (PTMs). This review dissects phosphorylation, acetylation, methylation, ubiquitination, glycosylation, and other PTMs of Hsp70 and Hsp90 across systems. These PTMs regulate the ATPase activity, localization, and interactions of the molecular chaperones with major implications in health and disease. The term "chaperone code" describes the PTM landscape that fine-tunes chaperone function. This code governs client fate, drug sensitivity, and stress responses. Importantly, combinatorial PTMs introduce regulatory complexity and flexibility, especially in cancer, neurodegeneration, and inflammation. The crosstalk between various PTMs and feedback loops add new regulatory layers to chaperone function. Additionally, these PTMs impact the function of the clients that are central in regulating specific cellular processes or pathways, such as transcription, autophagy, metabolism, and immune regulation. These pathways are usually affected in different maladies, such cancer, neurodegenerative, infectious and chronic diseases. Unlocking the chaperone code is essential for directing chaperone activity toward therapeutic benefit. This can be achieved by targeting enzymes that write, erase, or read the chaperone code, thereby offering new therapeutic strategies.
分子伴侣通过协助蛋白质折叠、稳定性和活性来维持蛋白质稳态。热休克蛋白70（Hsp70）和热休克蛋白90（Hsp90）是依赖ATP的伴侣蛋白，对蛋白质质量控制、信号传导和应激适应至关重要。它们的活性不仅受共伴侣蛋白的控制，还受动态翻译后修饰（PTM）的调控。本综述剖析了跨系统的Hsp70和Hsp90的磷酸化、乙酰化、甲基化、泛素化、糖基化及其他PTM。这些PTM调节分子伴侣的ATP酶活性、定位以及与主要健康和疾病影响相关的相互作用。术语“伴侣蛋白密码”描述了微调伴侣蛋白功能的PTM格局。这个密码决定了客户蛋白的命运、药物敏感性和应激反应。重要的是，组合PTM引入了调控的复杂性和灵活性，尤其是在癌症、神经退行性疾病和炎症中。各种PTM之间的串扰和反馈回路为伴侣蛋白功能增加了新的调控层次。此外，这些PTM影响着在调节特定细胞过程或途径（如转录、自噬、代谢和免疫调节）中起核心作用的客户蛋白的功能。这些途径通常在不同疾病（如癌症、神经退行性疾病、传染病和慢性病）中受到影响。解开伴侣蛋白密码对于将伴侣蛋白活性导向治疗益处至关重要。这可以通过靶向写入、擦除或读取伴侣蛋白密码的酶来实现，从而提供新的治疗策略。
