Prasad Vibhu
Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
mBio. 2025 Feb 5;16(2):e0352224. doi: 10.1128/mbio.03522-24. Epub 2025 Jan 8.
The unfolded protein response (UPR) is a cell-autonomous stress response aimed at restoring homeostasis due to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Viruses often hijack the host cell machinery, leading to an accumulation of misfolded proteins in the ER. The cell-autonomous UPR is the immediate response of an infected cell to this stress, aiming to restore normal function by halting protein translation, degrading misfolded proteins, and activating signaling pathways that increase the production of molecular chaperones. The cell-non-autonomous UPR involves the spreading of UPR signals from initially stressed cells to neighboring unstressed cells that lack the stressor. Though viruses are known modulators of cell-autonomous UPR, recent advancements have highlighted that cell-non-autonomous UPR plays a critical role in elucidating how local infections cause systemic effects, thereby contributing to disease symptoms and progression. Additionally, by utilizing cell-non-autonomous UPR, viruses have devised novel strategies to establish a pro-viral state, promoting virus spread. This review discusses examples that have broadened the understanding of the role of UPR in virus infections and disease progression by looking beyond cell-autonomous to non-autonomous processes and mechanistic details of the inducers, spreaders, and receivers of UPR signals.
未折叠蛋白反应（UPR）是一种细胞自主应激反应，旨在应对内质网（ER）中错误折叠蛋白积累导致的内环境稳态失衡。病毒常常劫持宿主细胞机制，致使内质网中错误折叠蛋白聚集。细胞自主的UPR是受感染细胞对这种应激的即时反应，旨在通过暂停蛋白质翻译、降解错误折叠蛋白以及激活增加分子伴侣产生的信号通路来恢复正常功能。细胞非自主的UPR涉及UPR信号从最初受应激的细胞传播至缺乏应激源的邻近未受应激细胞。虽然病毒是细胞自主UPR的已知调节因子，但最近的进展突出表明，细胞非自主UPR在阐明局部感染如何引发全身效应从而导致疾病症状和进展方面起着关键作用。此外，通过利用细胞非自主UPR，病毒已设计出建立促病毒状态、促进病毒传播的新策略。本综述通过超越细胞自主过程，探讨UPR信号诱导物、传播者和接受者的非自主过程及机制细节，讨论了拓宽对UPR在病毒感染和疾病进展中作用理解的实例。
