Phase separation as a new form of regulation in innate immunity

Abstract

Innate immunity is essential for the host against pathogens, cancer, and autoimmunity. The innate immune system encodes many sensor, adaptor, and effector proteins and relies on the assembly of higher-order signaling complexes to activate immune defense. Recent evidence demonstrates that many of the core complexes involved in innate immunity are organized as liquid-like condensates through a mechanism known as phase separation. Here, we discuss phase-separated condensates and their diverse functions. We compare the biochemical, structural, and mechanistic details of solid and liquid-like assemblies to explore the role of phase separation in innate immunity. We summarize the emerging evidence for the hypothesis that phase separation is a conserved mechanism that controls immune responses across the tree of life. The discovery of phase separation in innate immunity provides a new foundation to explain the rules that govern immune system activation and will enable the development of therapeutics to treat immune-related diseases properly.

Keywords: DNA sensing; LLPS; RNA sensing; cGAS-STING signaling; evolution; innate immunity; phase separation.