Phase separation is regulated by post-translational modifications and participates in the developments of human diseases

Abstract

Liquid-liquid phase separation (LLPS) of intracellular proteins has emerged as a hot research topic in recent years. Membrane-less and liquid-like condensates provide dense spaces that ensure cells to high efficiently regulate genes transcription and rapidly respond to burst changes from the environment. The fomation and activity of LLPS are not only modulated by the cytosol conditions including but not limited to salt concentration and temperture. Interestingly, recent studies have shown that phase separation is also regulated by various post-translational modifications (PTMs) through modulating proteins multivalency, such as solubility and charge interactions. The regulation mechanism is crucial for normal functioning of cells, as aberrant protein aggregates are often closely related with the occurrence and development of human diseases including cancer and nurodegenerative diseases. Therefore, studying phase separation in the perspective of protein PTMs has long-term significance for human health. In this review, we summarized the properties and cellular physiological functions of LLPS, particularly its relationships with PTMs in human diseases according to recent researches.

Keywords: Cancer; Condensates; Phase separation; Protein interactions; Protein post-translational modifications.

Fig. 1

The models showing the reversible process of liquid-liquid phase separation formation and the liquid behavious. (A) Diagram indicating the dynamic process of LLPS formation through weak multivalent interactions. (B) Diagram indicating two neighbouring small condensates could gradually fuse to a bigger one in minutes. (C) Diagram indicating the fluorescence recovery after photobleaching (FRAP): liquid-like condensate could recover after bleached by 488 nm laser. (D) Diagram indicating 1,6-hexanediol could disrupt the hydrophobic interactions and dissolve condensates.

Fig. 2

A model for RNA-mediated feedback control of transcriptional condensates. The low levels of RNA promote condensate formation at the early stage of transcription; as more and more RNAs are produced, high levels of RNA in turn promote the dissolution of condensate.

Fig. 3

Models and mechanisms showing the transition from liquid droplets to aggregated state. (A) Diagram indicating the liquid droplets formation of WT or G156E FUS and the transition into fibrous aggregates. Wild-type FUS protein forms reversible liquid-like condensates depending on transient weak multivalent interactions; while mutated FUS forms irreversible fibrous aggregates due to strong interactions. (B) Morphology images of WT and G156E FUS formed droplets in vitro through microscopy (From Simon Alberti [46]).

Fig. 4

The diagram of typical enhancer and super enhancer by LLPS. Typical enhancers are DNA cis-elements recruiting transcription factors, coactivators and the transcription apparatus to enhance gene transcription. Super-enhancers are clusters of enhancers achieved by the phase separation, recruiting high concentration of coactivators, transcription factors and transcription apparatus, which is mediated by IDRs depending on the multivalent interactions [4].