Two-Player Game in a Complex Landscape: 26S Proteasome, PKA, and Intracellular Calcium Concentration Modulate Mammalian Sperm Capacitation by Creating an Integrated Dialogue-A Computational Analysis

Abstract

Recent experimental findings suggest the involvement of the 26S proteasome, the main protease active in eukaryotic cells, in the process that leads mammalian sperm to become fully fertile, so-called capacitation. Unfortunately, its role in male gametes signaling is still far from being completely understood. For this reason, here, we realized a computational model, based on network theory, with the aim of rebuilding and exploring its signaling cascade. As a result, we found that the 26S proteasome is part of a signal transduction system that recognizes the bicarbonate ion as an input terminal and two intermediate layers of information processing. The first is under the control of the 26S proteasome and protein kinase A (PKA), which are strongly interconnected, while the latter depends on intracellular calcium concentrations. Both are active in modulating sperm function by influencing the protein phosphorylation pattern and then controlling several key events in sperm capacitation, such as membrane and cytoskeleton remodeling. Then, we found different clusters of molecules possibly involved in this pathway and connecting it to the immune system. In conclusion, this work adds a piece to the puzzle of protease and kinase crosstalk involved in the physiology of sperm cells.

Keywords: biological network; computational modeling; male gametes; protein phosphorylation; sperm capacitation; sperm signaling.

Figure 1

Hierarchical layout of 26SN. Representation of the network topology using a hierarchical layout that organizes the network depending on the direction of links. The blue circles indicate the controllers of information flux, which are implied in different layers of the signaling system.

Figure 2

Network representing the enrichment analysis carried out with STRING. The different colors represent different clusters: the main core of interconnected elements (yellow circle); phosphatases (blue circle); and ifit1, ifit3, and mx1, involved in interferon function (red circle).