Formation, function, and pathology of RNP granules

Abstract

Ribonucleoprotein (RNP) granules are diverse membrane-less organelles that form through multivalent RNA-RNA, RNA-protein, and protein-protein interactions between RNPs. RNP granules are implicated in many aspects of RNA physiology, but in most cases their functions are poorly understood. RNP granules can be described through four key principles. First, RNP granules often arise because of the large size, high localized concentrations, and multivalent interactions of RNPs. Second, cells regulate RNP granule formation by multiple mechanisms including posttranslational modifications, protein chaperones, and RNA chaperones. Third, RNP granules impact cell physiology in multiple manners. Finally, dysregulation of RNP granules contributes to human diseases. Outstanding issues in the field remain, including determining the scale and molecular mechanisms of RNP granule function and how granule dysfunction contributes to human disease.

Figure 1:. RNP granule examples.

A diverse set of ubiquitous, cell type-specific or stress induced RNP granules. Objects are not to scale and RNP granule numbers are not representative of cellular conditions.

Figure 2:. Prevalent Role of RNA.

A) Comparison of the average size of a SG enriched mRNA, an average mRNA and an average 55 kDa protein drawn to scale with size estimates from Khong and Parker, RNA, 2020. RNA bound RBPs are shown as colored circles. Estimates for the RBP number and RNA and protein surface area are indicated. B) Possible types of intermolecular RNA interactions.

Figure 3:. Common RNP granule properties.

A) Smaller RNP clusters exist below a critical concentration. Formation of larger granules is a cooperative process, triggered by an increase in protein-protein, protein-RNA and RNA-RNA interactions. B) Cooperative assembly could be driven by two energetic contributions: 1) Compared to smaller RNP clusters, larger clusters contain more binding sites leading to overall stronger RNP interactions through increased avidity. 2) RNPs inside granules display stronger intermolecular interactions compared to RNPs interacting with the solvent. C) After initial RNP granule formation, new additional interactions lead to the stabilization of the RNP granule. D) Interactions between homotypic (the same granule) or heterotypic (two different) RNP granules lead to fusion or docking, respectively. Weak or stable homotypic RNP granule interactions lead to faster or slower fusion. E) Homotypic or heterotypic RNP interactions can also lead to subassemblies within a granule or lead to core shell architectures.

Figure 4:. Biophysical principles by which RNP granules could lead to function.

A) Increase in high local concentration could lead to increase in reaction or assembly rates. B) Sequestration or sponging biomolecules into RNP granules could inhibit their activity in the cytoplasm or nucleoplasm. C) Transport of RNP granules for localized translation. D) Unique environments e.g. RNP granules could prevent irreversible aggregation of biomolecules.