Simulation of the endocytic and secretory pathways using Agent Based Model

NIETO, FRANCO; CEBRIÁN, IGNACIO; MAYORGA, LUIS S

Congreso; Congreso Argentino de Bioinformática y Biología Computacional; 2021

Background:Intracellular traffic is a central process in the cellular physiology. Numerous macromolecules must be transported in the endocytic and exocytic pathways for the correct function of a eukaryotic cell. However, the way by which macromolecules are transported between compartments is still a matter of intense debate. Intracellular transport occurs in dynamic organelles that merge, divide, and change position and shape, while altering their composition by complex networks of molecular interactions and chemical reactions. We are interested in cross-presentation in dendritic cells. These cells belong to the antigen-presenting cells group, and play a central role in linking innate sensing of pathogens and antigen processing to adaptive immune responses. Antigen cross-presentation consists of several steps. First, the antigenic proteins are internalized by endocytosis. Then, by still not well-characterized mechanism, these molecules are translocated to the cytosol for proteasome degradation. The resulting peptides are transported back to the phagosome and loaded onto Major Histocompatibility Class I complexes (MHC-I). Finally, the MHC-I/peptide complexes migrate to the plasma membrane to trigger a CD8+ T lymphocyte cytotoxic response.Results:Our group has developed a simulation of the endocytic pathway (early, late, sorting and recycling endosomes), based on a combination of agent-base modeling and ordinary differential equations. To simulate cross-presentation, we incorporated a secretory pathway, including the ER compartment, ERGIC, three Golgi cisternae and a Trans Golgi Network. The model also considered plasma membrane and cytosolic compartments. This complex endomembrane system was able to reproduce antigen internalization, translocation to the cytosol, processing to peptides, incorporation to membrane-bound organelles and transport to the plasma membrane. The parameters of the simulations were adjusted by experimental results; nevertheless, more empirical data will be required to specify the parameter for each step of cross-presentation. All compartments preserved their identity and functionality for more than 300.000 ticks (equivalent to 5 hs. of cellular life). These results show that an endomembrane system able to reproduce complex processes that strongly depends on cargo trafficking can be organized by the interaction of individual agents following simple rules.Conclusions:This modeling strategy successfully reproduces transport in the endocytic and secretory pathways and the slow appearance of MHC-I complexes loaded with peptide on the cell surface. We expect that the active dialogue between simulations and experimental results will foster our understanding of the logic underlying the transport mechanisms that efficiently sort a large number of macromolecules to their final destination inside and outside the cell.