Liquid-liquid separation in gut immunity

Abstract

Gut immunity is essential for maintaining intestinal health. Recent studies have identified that intracellular liquid-liquid phase separation (LLPS) may play a significant role in regulating gut immunity, however, the underlying mechanisms remain unclear. LLPS refers to droplet condensates formed through intracellular molecular interactions, which are crucial for the formation of membraneless organelles and biomolecules. LLPS can contribute to the formation of tight junctions between intestinal epithelial cells and influence the colonization of probiotics in the intestine, thereby protecting the intestinal immune system by maintaining the integrity of the intestinal barrier and the stability of the microbiota. Additionally, LLPS can affect the microclusters on the plasma membrane of T cells, resulting in increased density and reduced mobility, which in turn influences T cell functionality. The occurrence of intracellular LLPS is intricately associated with the initiation and progression of gut immunity. This review introduces the mechanism of LLPS in gut immunity and analyzes future research directions and potential applications of this phenomenon.

Keywords: condensate; gut immunity; immune cell; inflammatory bowel disease; liquid-liquid separation.

Figure 1

Different forms of liquid-liquid separation in gut cells. LLPS in gut cells are formed by the interaction of macromolecular proteins, RNA, DNA, etc., including protein and protein, DNA and protein, DNA and DNA, RNA and RNA, RNA and protein. In addition, LLPS also participates in the formation of some membraneless organelles in cells, such as P body, stress granule (SG), nucleolus, etc.

Figure 2

Different ways in which liquid-liquid separation is involved in gut immunity. (A) ZO-1, Claudin, Occludin and other proteins in intestinal epithelial cells can use ZO-1 as a scaffold to generate LLPS and participate in the formation of intestinal barrier. (B) LLPS between Rho proteins in gut microorganisms is involved in colonization of gut microorganisms. (C) LLPS of SLP65 and SIN85 proteins in gut immune cells (B cells) is involved in gut immune regulation.

Figure 3

The mechanism of liquid-liquid separation involved in NF-κB signaling pathways. In gut immune cells, negatively charged DNA can bind to positively charged cGAS to form LLPS, which prevents the degradation of DNA by TREX1 and passes the signal downstream to cGAMP. Further, cGAMP activated STING and TBK1, which interact to form LLPS, thereby promoting the activation of NF-κB. On the other hand, when RNA viruses infect the gut, viral RNA can bind to TAK1 and IKKβ to form LLPS, further promoting the activation of NF-κB. Eventually, inflammatory factors are expressed and an immune response is generated.