Droplets of life: role of phase separation in virus replication and compartmentalization

Liquid–liquid phase separation (LLPS), a process leading to the formation of a condensed phase surrounded by a dispersed phase, has attracted much attention considering the multitude of physiological and pathological processes in which it is involved. LLPS drives the formation of membrane-less organelles (MLOs) (e.g., cajal bodies, processing bodies, nucleolus, SGs, centrosomes, and aggresomes), whose functions are essential for the cell and whose dysfunction is associated with various pathologies, including age-related disorders. These biological condensates play a critical role in the spatiotemporal organization of the cell, where they exert a multitude of key biological functions, ranging from transcriptional regulation and silencing to the control of signal transduction networks. Viruses also exploit LLPS for their replication either by interfering with assembly and disassembly of host MLOs or by eliciting the formation of virus-specific condensates. After introducing the general principles of LLPS and its connection with gelation and fibrillation, we herein survey available data on LLPS by viral proteins and discuss their functional implications. We distinguish LLPS associated with viral replication and trafficking of viral components, from the LLPS-mediated interference of viruses with host cell functions. Among LLPSs of the former class, we focus mainly, though not exclusively, on examples provided by Mononegavirales members. We discuss the connection between virus and amyloids and review the few results describing viral amyloids. We discuss emerging evidence on the ability of plant virus proteins to either undergo LLPS or to interfere with the regulation of host MLOs, and propose that bacteriophages can interfere with bacterial LLPS, as well. We conclude by discussing how LLPS could be targeted to treat phase separation-associated diseases, including viral infections.