Laboratório de Virologia Básica e Aplicada, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Pampulha, Belo Horizonte 31270-901, MG, Brazil.
CT Terapias Avançacadas e Inovadoras, CTERAPIAS, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.
Viruses. 2024 Sep 30;16(10):1555. doi: 10.3390/v16101555.
In eukaryotic cells, the endoplasmic reticulum is particularly important in post-translational modification of proteins before they are released extracellularly or sent to another endomembrane system. The correct three-dimensional folding of most proteins occurs in the ER lumen, which has an oxidative environment that is essential for the formation of disulfide bridges, which are important in maintaining protein structure. The ER is a versatile organelle that ensures the correct structure of proteins and is essential in the synthesis of lipids and sterols, in addition to offering support in the maintenance of intracellular calcium. Consequently, the cells needed to respond to demands caused by physiological conditions and pathological disturbances in the organelle homeostasis, leading to proper functioning of the cell or even programmed cell death. Disturbances to the ER function trigger a response to the accumulation of unfolded or misfolded proteins, known as the unfolded protein response. Such disturbances include abiotic stress, pharmacological agents, and intracellular pathogens, such as viruses. When misfolded proteins accumulate in the ER, they can undergo ubiquitination and proteasomal degradation through components of the ER-associated degradation system. Once a prolonged activity of the UPR pathway occurs, indicating that homeostasis cannot be reestablished, components of this pathway induce cell death by apoptosis. Here, we discuss how viruses have evolved ways to counteract UPR responses to maximize replication. This evolutionary viral ability is important to understand cell pathology and should be taken into account when designing therapeutic interventions and vaccines.
在真核细胞中，内质网在蛋白质被释放到细胞外或被送到另一个内膜系统之前的翻译后修饰中尤为重要。大多数蛋白质的正确三维折叠发生在内质网腔中，内质网腔具有氧化环境，这对于形成二硫键至关重要，二硫键对于维持蛋白质结构很重要。内质网是一种多功能细胞器，可确保蛋白质的正确结构，并在脂质和固醇的合成中必不可少，此外还可在维持细胞内钙方面提供支持。因此，细胞需要对细胞器稳态中生理条件和病理干扰引起的需求做出反应，以确保细胞的正常功能甚至程序性细胞死亡。内质网功能的紊乱会引发对未折叠或错误折叠蛋白质的积累的反应，称为未折叠蛋白反应。这种紊乱包括非生物应激、药理学制剂和细胞内病原体，如病毒。当错误折叠的蛋白质在内质网中积累时，它们可以通过内质网相关降解系统的组件进行泛素化和蛋白酶体降解。一旦 UPR 途径的长时间活性发生，表明稳态不能重新建立，该途径的组件通过细胞凋亡诱导细胞死亡。在这里，我们讨论了病毒如何进化出对抗 UPR 反应的方法，以最大限度地提高复制。这种进化的病毒能力对于理解细胞病理学很重要，在设计治疗干预和疫苗时应考虑到这一点。
