Emerging Roles of Ubiquitination in Biomolecular Condensates

Abstract

Biomolecular condensates are dynamic non-membrane-bound macromolecular high-order assemblies that participate in a growing list of cellular processes, such as transcription, the cell cycle, etc. Disturbed dynamics of biomolecular condensates are associated with many diseases, including cancer and neurodegeneration. Extensive efforts have been devoted to uncovering the molecular and biochemical grammar governing the dynamics of biomolecular condensates and establishing the critical roles of protein posttranslational modifications (PTMs) in this process. Here, we summarize the regulatory roles of ubiquitination (a major form of cellular PTM) in the dynamics of biomolecular condensates. We propose that these regulatory mechanisms can be harnessed to combat many diseases.

Keywords: autophagy; biomolecular condensates; liquid–liquid phase separation; stress granules; ubiquitin.

Figure 1

Stress-granule dynamics are tightly regulated by ubiquitination. Cells under stress inhibit the translation initiation of mRNAs, leading to stress granules’ formation that involves the phase separation of RBPs (such as G3BP1, T-cell intracellular antigen 1 (TIA-1), ELAV-like protein 1 (HuR), TIA1-related protein (TIAR) etc.) and mRNAs. Both the assembly and disassembly of stress granules are regulated by PTMs, including ubiquitination. The disassembly of stress granules is enhanced through the K63-linked ubiquitination of G3BP1, subsequently fostering the interaction between ubiquitin chains and VCP. Mutations in RBPs or prolonged stress cause the transition of stress granules into pathological aggregates. Ubiquitination governs the clearance of these aggregates, with K48-linked ubiquitin chains directing degradation through the ubiquitin-proteasome system (UPS), whereas K63-linked ubiquitination is associated with the autophagic degradation pathways. Created with BioRender.com.

Figure 2

The process of autophagic cargo segregation is driven by poly-ubiquitin chain-induced p62 phase separation. p62 protein forms oligomers via the PB1 domain and also binds to ubiquitin through the UBA domain. Upon reaching the threshold concentration required for LLPS, the formation of p62 condensates occurs. Subsequently, other client proteins are recruited to these p62 condensates that further mature and ultimately are broken down through autophagy. Created with BioRender.com.