Advances and development proposals on biomacromolecular phase separation research

Abstract

Biomacromolecular phase separation or phase transition is a cutting-edge area of biological research which has been rapidly developing in recent years. Cellular liquid-liquid phase separation, which is mediated by related biomacromolecules, drives the formation of many membrane-less compartments, such as nucleoli, centromeres, centrosomes, P granules, stress granules (SGs) and some signal transduction complexes. These biomolecular condensates are micron-scale membrane-less compartments in cells that function to concentrate biomacromolecules and they originate from liquid-liquid phase separation (LLPS), which is driven by multivalent interactions among biomacromolecules, including proteins and nucleic acids. Biomacromolecular phase separation has extensive biological functions. First, it regulates biochemical reactions in cells. For example, concentrating reactants inside biomolecular condensates can change reaction kinetics and substrate specificities. Second, it allows for fast changes in molecules upon sensing and responding to stress. Third, it can buffer cellular concentrations of biomacromolecules. Finally, it allows direct communication between membrane-less and membrane-bound organelles. Aberrant phase separation has been proven to be associated with many human diseases. Proteins involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are components of biomolecular condensates. Dysregulation in the formation of these components leads to pathological aggregates. Aberrant phase separation is also involved in cancer. An example is the tumor suppressor speckle-type POZ protein (SPOP), which is involved in the ubiquitination and proteasomal degradation of related substrates. The substrates are proto-oncogenic proteins that trigger phase separation of SPOP and its co-localization in a membrane-less compartment. Mutations in SPOP that interfere with its substrate interactions cause prostate and breast cancer, as well as other solid tumors. Emerging evidence suggests that aberrant phase separation is also related to infectious diseases. For example, many viruses produce factors that inhibit SG formation or promote changes in SG composition that suppress cellular stress responses and promote viral replication. Therefore, targeting the regulators of phase separation could be a promising therapeutic approach for these human diseases. Although there have been rapid developments in biomacromolecular phase separation worldwide, this emerging field has attracted increased attention in China over the past 5 years. A series of outstanding achievements have established a prominent role for China in the international community of biomacromolecular phase separation research. Moreover, many excellent research teams have been established in Chinese universities and institutes. Currently, China is in a critical period of striving to be at the international frontier of biomacromolecular phase separation research. To further enhance China’s advantage in this emerging field, the following developmental proposals are discussed in this review: (1) Establishing academic research standards for biomacromolecular phase separation; (2) enhancing interdisciplinary research and developing a biomacromolecular phase separation theory; (3) developing related cutting-edge technologies and methods; (4) strengthening functional in vivo studies for biomacromolecular phase separation that elucidate the underlying molecular mechanisms and their relationships with human diseases; and (5) gathering outstanding scientists through the full utilization of academic organizations.