Actin is a key protein of the muscle contraction system. It is present in the cytoplasm, providing motor and framework function through polymerization into F-actin, as well as in the nuclei of all non-muscle cells, where most actin is present in a globular form and participates in processes related to the cell's genetic apparatus, including transcription and DNA repair. Actin interacts with a large number of proteins that form a whole class of actin-binding proteins. Since the functional role of nuclear actin differs significantly from the role of actin in the cell cytoplasm, the goal of this study was to compare the interactome of cytoplasmic and nuclear actin.

Using the BioGRID and StringDB databases, proteins that interact with actin experimentally confirmed were selected. Four groups of actin-binding proteins were identified depending on their cellular localization: only cytoplasm, only nucleus, and nucleus and cytoplasm, and others. The analysis of biological processes in the interactome showed that nuclear proteins participate in most key nuclear processes,from DNA damage response to transcription regulation, while cytoplasmic actin-binding proteins are involved in the formation, regulation, and functioning of the cytoskeleton. The analysis of the structure of actin-binding proteins showed a large proportion of internally disordered proteins, most of which are part of membraneless organelles (MLOs). It is known that proteins prone to liquid–liquid phase separation (LLPS) play a key role in the formation of MLOs. Interestingly, although significantly more nuclear proteins are prone to LLPS than cytoplasmic proteins (44% vs. 25%), the drivers of the formation of MLOs in the cytoplasm are significantly (four times) more than in the nucleus. From the pool of actin-binding proteins, 28 clusters were identified, within each of which proteins are capable of forming physical contacts with each other.

The work was supported by the Russian Science Foundation (project No. 23-15-00494, IMK).