Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milano, Italy.
Laboratoire Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Aix Marseille University and CNRS, 13288 Marseille, France.
Int J Mol Sci. 2023 Jan 21;24(3):2151. doi: 10.3390/ijms24032151.
Liquid-liquid phase separation (LLPS) is responsible for the formation of so-called membrane-less organelles (MLOs) that are essential for the spatio-temporal organization of the cell. Intrinsically disordered proteins (IDPs) or regions (IDRs), either alone or in conjunction with nucleic acids, are involved in the formation of these intracellular condensates. Notably, viruses exploit LLPS at their own benefit to form viral replication compartments. Beyond giving rise to biomolecular condensates, viral proteins are also known to partition into cellular MLOs, thus raising the question as to whether these cellular phase-separating proteins are of LLPS or behave as . Here, we focus on a set of eukaryotic proteins that are either sequestered in viral factories or colocalize with viral proteins within cellular MLOs, with the primary goal of gathering organized, predicted, and experimental information on these proteins, which constitute promising targets for innovative antiviral strategies. Using various computational approaches, we thoroughly investigated their disorder content and inherent propensity to undergo LLPS, along with their biological functions and interactivity networks. Results show that these proteins are on average, though to varying degrees, enriched in disorder, with their propensity for phase separation being correlated, as expected, with their disorder content. A trend, which awaits further validation, tends to emerge whereby the most disordered proteins serve as , while more ordered cellular proteins tend instead to be of viral factories. In light of their high disorder content and their annotated LLPS behavior, most proteins in our data set are or of molecular condensation, foreshadowing a key role of these cellular proteins in the scaffolding of viral infection-related MLOs.
液-液相分离 (LLPS) 负责形成所谓的无膜细胞器 (MLO)，这对于细胞的时空组织至关重要。无序蛋白 (IDP) 或区域 (IDR)，无论是单独存在还是与核酸结合，都参与这些细胞内凝聚物的形成。值得注意的是，病毒利用 LLPS 为自身利益形成病毒复制隔间。除了引发生物分子凝聚物外，病毒蛋白也已知分配到细胞的 MLO 中，这就提出了一个问题，即这些细胞相分离蛋白是 LLPS 的一部分还是表现为功能性蛋白质。在这里，我们专注于一组真核蛋白，这些蛋白要么被隔离在病毒工厂中，要么与细胞内 MLO 中的病毒蛋白共定位，主要目标是收集这些蛋白的有组织、可预测和实验信息，这些蛋白构成了创新抗病毒策略的有前途的靶标。使用各种计算方法，我们彻底研究了它们的无序含量和固有发生 LLPS 的倾向，以及它们的生物学功能和相互作用网络。结果表明，这些蛋白的无序性平均而言，尽管程度不同，但都有所富集，其相分离倾向与无序含量呈正相关。一个有待进一步验证的趋势是，最无序的蛋白倾向于充当分子凝聚物的一部分，而更有序的细胞蛋白则倾向于充当病毒工厂的一部分。鉴于它们的高无序含量和注释的 LLPS 行为，我们数据集中的大多数蛋白要么是分子凝聚物的一部分，要么是功能性蛋白质，预示着这些细胞蛋白在病毒感染相关 MLO 的支架中发挥关键作用。
