Liquid-liquid phase separation in innate immunity

Abstract

Intrinsic and innate immune responses are essential lines of defense in the body's constant surveillance of pathogens. The discovery of liquid-liquid phase separation (LLPS) as a key regulator of this primal response to infection brings an updated perspective to our understanding of cellular defense mechanisms. Here, we review the emerging multifaceted role of LLPS in diverse aspects of mammalian innate immunity, including DNA and RNA sensing and inflammasome activity. We discuss the intricate regulation of LLPS by post-translational modifications (PTMs), and the subversive tactics used by viruses to antagonize LLPS. This Review, therefore, underscores the significance of LLPS as a regulatory node that offers rapid and plastic control over host immune signaling, representing a promising target for future therapeutic strategies.

Keywords: DNA sensing; LLPS; PTMs; RNA sensing; immune signaling; innate immunity; membraneless organelles; phase separation; post-translational modification; proteomics; viral infection.

Fig. 1.. LLPS states o and their contribution to mammalian innate immunity.

The diagram shows: (A) LLPS exhibits different material states, ranging from liquid droplet, gel, to filament. The insets provide examples of host immune factors displaying distinct LLPS states. (B) Shown are molecular drivers of LLPS, mediated by multivalent domains or intrinsically disordered regions, with specific examples listed in the insets. π-π or charge-π denotes the type of interactions formed by π-bonds, often seen in aromatic residues [1]. (C) Depicted is the functional importance of LLPS in the context of innate immunity. Two major means by which LLPS can regulate innate immunity are (1) reaction crucibles that enable efficient enzymatic reactions and signaling responses, and (2) as sequestration hubs that selectively exclude/recruit key signaling molecules to regulate signaling, a strategy that can also be co-opted by pathogens for immune evasion. Abbreviations: SH, Src homology; PRM, proline-rich motifs; pY, tyrosine phosphorylation; SIM, SUMO-interacting motif; SGs, stress granules.

Fig. 2 (Key Figure).. Known mammalian innate immunity pathways regulated by LLPS.

Highlighted within an immune cell such as THP-1, is the reported involvement of LLPS in DNA [–,–16,23]and RNA sensing [,,–51], inflammasome signaling [53,56], and the formation of cytoplasmic or nuclear granules [,,,,–169]. Examples shown are discussed in detail in relevant sections of the main text. Viral proteins known to suppress LLPS-mediated immune responses are depicted [,,–,–75]. The contributions of posttranslational modifications in either promoting or inhibiting LLPS are represented for each pathway [10,19,23,59,115]. LLPS-capable protein indicates that the protein was directly reported to undergo LLPS; LLPS client/regulator might not directly undergo LLPS, but has been reported to be recruited into LLPS condensates or modulate LLPS formation or activities.