Friends or foes: dissecting the crosstalk between stress granules and viruses during infection

Living organisms must respond rapidly to environmental changes in nutrients, temperature, oxygen and also to infection and signals such as hormones. This is frequently mediated by limiting the energy hungry process of protein synthesis in a pause and adapt approach. This is achieved by sending signals throughout the cell to communicate a state of emergency leading to coordinated and widespread changes in the cell. This allows for an overhaul of proteins to favour proteins that facilitate survival under the new conditions. A key to this adaptation is the formation of membraneless organelles called stress granules which are a universal first line response to stress.
Textbook biology defines lipid bilayer membrane wrapping organelles, such as the endoplasmic reticulum or mitochondria, as the main organising principle of a cell. However, the identification of membraneless organelles presents a new paradigm for cell biology. Membraneless organelles are perfectly suited to rapid adaptation to stress as by sequestering nucleic acids and proteins in specific compartments they can speed up reactions between their components or act as temporary storage sites. Stress granules (SGs) are a paradigm for membraneless organelles and the focus of this research project.
Several functions have been proposed for SGs. First, they help sort and compartmentalize cellular mediator such as nucleic acids and proteins defining those needed to adapt to the new conditions and those which are superfluous.Second, they store proteins that can send signals to trigger specific responses to the stress. Third, they are important in diseases; if dysregulated SGs can also contribute to diseases of the brain, cancer and impact on the outcome of viral diseases. Despite their evident importance in human disease, major unsolved questions remain about how SGs function during viral infections. Research including our own has shown that SGs can be both pro and anti- viral. They are a universal first line response to stress, and can select components with antiviral activities, yet some viruses induce SGs that appear to benefit their replication. However, there is little information about the mechanisms underpinning this.
We have pioneered studies into these critical membraneless organelles and using our expertise in isolating and imaging these organelles, and novel tools, we are poised to elucidate how SGs mediate pro and anti-viral responses. Our research program will comprehensively fingerprint SGs formed within cells infected by different viruses to identify their components, interactions, and functions. We will uncover the molecular mechanisms by which SGs contribute to cellular defences against viruses and define how some viruses can also hijack these organelles to promote their own replication.
Ultimately, the outcome of this work will advance our understanding of novel and fundamental aspects of cell biology and importantly relate this to pathological conditions and therefore this work will contribute to long and healthy living.

Phase separation is emerging as a key regulatory principle in eukaryotes. The assembly and dissolution of membraneless organelles such as stress granules provides a switch-like regulation of the activities of their RNA and protein components. However, many fundamental questions about the biological functions of these biocondensates remain. Our overarching aim is to establish the role of stress granules during viral infections, uncovering the mechanisms by which they specialise in response to viruses and the molecular basis for their pro- or anti-viral functions.
We will take advantages of virus models that induce the assembly of stress granules with either pro-viral or anti-viral functions. First, we will determine how viruses trigger the assembly of heterogeneous stress granules with distinct functions by establishing their structure, dynamics and composition. We will use high-throughput imaging and biochemical isolation of stress granules coupled to proteomics to define these virus-specific variations. In addition, we will build on our recent findings that canonical stress granules contain reactive species and characterise their presence in virus-induced stress granules. Next, we will identify the molecular mechanisms by which stress granules contribute to viral replication and regulate antiviral signalling in infected cells. Informed by the proteomics we will identify the cellular pathways responsible for the crosstalk between virus and stress granules, the specific stress granules proteins involved and the contribution of reactive species using targeted approaches.
Our study will establish guiding principles for how stress granules specialise in response to viruses, uncovering novel and fundamental aspect of stress granules biology that underpin essential virus-host interactions.