Understanding the crosstalk between spatially separated RNP granules during cellular stress responses

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Phase separation is emerging as a key regulatory principle in eukaryotes, with the assembly and dissolution of membraneless organelles allowing the switch-like regulation of their RNA and protein components activities. Our overarching aim is to understand how RNP granules shape the cellular response to adverse conditions, uncovering how they specialise during stress to exert a specific response and mechanisms of their crosstalk under conditions of spatial segregation.
Given their role in healthy responses and their deregulation in diseases such as viral infections and neurodegeneration, we will use stress granules and paraspeckles as prototypical RNP granules for cytoplasmic and nuclear membraneless organelles. First, we will determine how different stresses trigger the assembly of heterogeneous stress granules and paraspeckles with distinct functional flavours by establishing their structure, dynamics and composition. We will use high-throughput imaging and biochemical isolation of RNP granules coupled to proteomics to define the stress-specific properties of these RNP granules. Next and building on our recent evidence that stress granules can regulate paraspeckles assembly, we will identify the mechanisms responsible for this crosstalk by characterising the signalling pathways and specific proteins involved using both screening and targeted approaches informed by the proteomics. Finally, we will reveal how the assembly of aberrant stress granules impacts on paraspeckles and cellular functions in neurons using models of neurodegenerative diseases; and how the crosstalk between stress granules and paraspeckles contributes to antiviral signalling in infected cells, using viruses known to induce stress granules.
Our study will establish guiding principles for how membraneless organelles specialise and communicate in healthy and pathological conditions, uncovering novel rules of cellular adaptation during stress.