Abstract
A common viral replication strategy is characterized by the assembly of intracellular compartments that concentrate factors needed for viral replication and simultaneously conceal the viral genome from host-defense mechanisms. Recently, various membrane-less virus-induced compartments and cellular organelles have been shown to represent biomolecular condensates (BMCs) that assemble through liquid-liquid phase separation (LLPS). In the present work, we analyze biophysical properties of intranuclear replication compartments (RCs) induced during human adenovirus (HAdV) infection. The viral ssDNA-binding protein (DBP) is a major component of RCs that contains intrinsically disordered and low complexity proline-rich regions, features shared with proteins that drive phase transitions. Using fluorescence recovery after photobleaching (FRAP) and time-lapse studies in living HAdV-infected cells, we show that DBP-positive RCs display properties of liquid BMCs, which can fuse and divide, and eventually form an intranuclear mesh with less fluid-like features. Moreover, the transient expression of DBP recapitulates the assembly and liquid-like properties of RCs in HAdV-infected cells. These results are of relevance as they indicate that DBP may be a scaffold protein for the assembly of HAdV-RCs and should contribute to future studies on the role of BMCs in virus-host cell interactions.
Highlights
We show that the human adenovirus (HAdV)-replication compartments (RCs) can be described as viral biomolecular condensates (BMCs) with liquid-like properties that can be conferred by DBP
Where viral ssDNA and dsDNA, as well as viral early unspliced and spliced mRNAs, are localized [7,17,23,72,73,74]. This process is initiated as soon as this viral early protein is imported into the nucleus during the early phase of viral replication, when the protein is distributed in small intranuclear foci (Figure 1A, 16–20 hpi)
As described in the introduction, DBP is one of the main components of adenovirus RCs and participates directly in viral genome replication, and in different aspects of viral mRNA biogenesis, activities that are associated with RCs [23]
Summary
Human adenoviruses (HAdVs) from species B, C and E are the causative agents of 5–10% of acute respiratory infections in children [2,3], and can cause pneumonia, which can be fatal in immunocompromised patients—where the fatality rate can be 50% or higher—and in healthy children and adults [4]. HAdVs are clinically relevant viruses, there are no specific treatments, or vaccines available to the general public. Besides their relevance as human pathogens, adenoviruses are one of the most commonly used viral vectors in the design and development of vaccines, as well as gene and combined anticancer therapies [5,6]. Adenoviruses have been used as a model system to study eukaryotic cellular processes, such as transcription, post-transcriptional processing, nuclear organization, cell cycle control and cell death [7,8]
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