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Phase separation in immune signalling

Abstract

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.

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Fig. 1: Phase separation in three dimensions and two dimensions.
Fig. 2: A microcluster view of T cell receptor signalling.
Fig. 3: Signalling condensates in the B cell receptor pathway.
Fig. 4: Phase separation of intracellular innate immune signalling pathways.

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Acknowledgements

X.S. has received support from an American Cancer Society Institutional Research Grant, the Charles H. Hood Foundation Child Health Research Awards Program, an Andrew McDonough B+ Foundation research grant, the Gilead Sciences Research Scholars Program in Hematology/Oncology, the Rally Foundation and Bear Necessities Foundation Collaborative Pediatric Cancer Research Awards Program, a Yale SPORE in Skin Cancer Development Research Program Award, a Yale DeLuca Pilot Award and the NIGMS MIRA (R35) programme (GM138299).

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Xiao, Q., McAtee, C.K. & Su, X. Phase separation in immune signalling. Nat Rev Immunol (2021). https://doi.org/10.1038/s41577-021-00572-5

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