P.1 和 P.2 SARS-CoV-2 巴西变种激活了展开的蛋白质反应,具有时间和途径特异性
Vinícius de Morais Gomes1, Deivid Martins Santos1, Janaina Macedo-da-Silva1
1GlycoProteomics Laboratory, Department of Parasitology, ICB, University of São Paulo, Brazil.
Journal of proteomics
|February 5, 2025
概括
巴西的SARS-CoV-2变种诱导了细胞内膜网膜的压力,并激活了未折叠的蛋白质反应 (UPR). 调节UPR减少病毒释放,突出显示UPR是COVID-19的治疗目标.
科学领域:
- 病毒学 病毒学
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
背景情况:
- 严重急性呼吸系统综合征冠状病毒2 (SARS-CoV-2) 变种,包括巴西的玛 (P.1) 和泽塔 (P.2),表现出增加的传染性和毒性.
- 病毒感染可以破坏宿主细胞机械,特别是内细胞网 (ER) 中的蛋白质折叠和加工.
- ER功能障碍导致ER压力,触发未折叠蛋白质反应 (UPR) 以恢复平衡或启动亡.
研究的目的:
- 调查巴西SARS-CoV-2变种在感染细胞中激活的分子机制.
- 为了确定UPR调制是否可以抵消病毒复制和释放.
- 探索ER压力标志物与患者COVID-19进展之间的相关性.
主要方法:
- 对感染SARS-CoV-2的细胞系进行蛋白质和免疫阻塞分析.
- 药理学调节的UPR路径.
- 人类临床标本的转录组分析.
- 对ER相关基因与COVID-19疾病结果的相关性分析.
主要成果:
- 巴西SARS-CoV-2变种 (和泽塔) 诱导了显著的ER压力,并激活了受感染细胞中的UPR通路.
- 特定的变体表现出UPR的独特调制.
- 药理UPR调节有效地减少了感染细胞中的病毒释放,而不会影响细胞活力.
- 转录组数据显示了ER相关基因与COVID-19进展之间的相关性.
结论:
- SARS-CoV-2 变种,特别是巴西菌株,利用 ER 压力和 UPR 途径进行复制.
- 准UPR代表了一种有前途的宿主导治疗策略,用于对抗SARS-CoV-2感染.
- 了解ER压力调节对于开发针对COVID-19变种的有效治疗至关重要.
相关概念视频
01:37The Unfolded Protein Response
4.4K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.4K
01:31Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
02:28Leaky Scanning
5.1K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.1K
01:13The Proteasome
803
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
803
01:29Protein Folding Quality Check in the RER
3.7K
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
3.7K
02:04Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K