Phase separation in immune signalling

Phase separation has emerged as a new biophysical principle for organizing biomolecules into large clusters with fluidic properties. Here, Su and colleagues summarize what we currently know about phase separation in immune cells and look to the future of this field in understanding the regulation of immune signalling. Immune signalling pathways convert pathogenic stimuli into cytosolic events that lead to the resolution of infection. Upon ligand engagement, immune receptors together with their downstream adaptors and effectors undergo substantial conformational changes and spatial reorganization. During this process, nanometre-to-micrometre-sized signalling clusters have been commonly observed that are believed to be hotspots for signal transduction. Because of their large size and heterogeneous composition, it remains a challenge to fully understand the mechanisms by which these signalling clusters form and their functional consequences. Recently, phase separation has emerged as a new biophysical principle for organizing biomolecules into large clusters with fluidic properties. Although the field is still in its infancy, studies of phase separation in immunology are expected to provide new perspectives for understanding immune responses. Here, we present an up-to-date view of how liquid-liquid phase separation drives the formation of signalling condensates and regulates immune signalling pathways, including those downstream of T cell receptor, B cell receptor and the innate immune receptors cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and retinoic acid-inducible gene I protein (RIG-I). We conclude with a summary of the current challenges the field is facing and outstanding questions for future studies.

Automated summary

Phase separation is a new biophysical principle in organizing biomolecules into fluidic clusters, with potential implications for immune signaling pathways. The formation of signaling condensates through liquid-liquid phase separation is crucial for understanding how immune responses are regulated in cells. Despite the challenges in fully understanding the mechanisms and functional consequences of these signaling clusters, studies in immunology are expected to provide new perspectives on immune responses.