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.

In Vitro Folliculogenesis in Mammalian Models: A Computational Biology Study

“…In addition, seeking for controllers of the information flow within the network, 38 bottleneck nodes were identified (BN: Supplementary File 4 ) ( Ordinelli et al, 2018 ) ( Taraschi et al, 2020 ).…”

“…The final WoS_MM iv F database contains 513 selected iv F-related manuscripts classified as original primary research articles (444/513; 87%) and reviews (69/;513; 13%), according to Taraschi et al ( Taraschi et al, 2020 ). The WoS_MM iv F database was enriched in Microsoft Excel 365 with the following fields ( Supplementary File 1 ): a) Source molecule: The molecule working as the source of interaction.…”

“…Bottlenecks (BN) were identified as follows: let Ts be a shortest path tree rooted at node s, BN(v) = Σs∈V ps(v). In detail, e ps(v) = 1 if more than |V(Ts)|/ 4 paths from node s to other nodes in Ts meet at the vertex v; otherwise ps(v) = 0 ( Chin et al, 2014 ) ( Taraschi et al, 2020 ) ( Ordinelli et al, 2018 ).…”

Mathematical model reveals that heterogeneity in the number of ion transporters regulates the fraction of mouse sperm capacitation

“…To our knowledge this is the first bottom to top capacitation model with the capability of incorporating and unraveling molecular mechanisms which intervene in the definition of regulatory relations that generate a dynamics for the study of temporal behavior. Previous modeling has been undertaken, which, with a top to bottom approach such as data-mining techniques focuses on determining the topology of prospective networks relevant to capacitation [59][60][61][62][63].…”

IP3R Channels in Male Reproduction

“…However, the expression and roles of IP3R in sperm mitochondria are still unknown. The redundant nuclear envelope (RNE), surrounding the axoneme at the base of the flagellum, provides the third Ca 2+ store in sperm involved in Ca 2+ mobilization [47]. Preliminary experimental evidence suggests that the RNE contains IP3R, which may regulate sperm hyperactivated motility [42].…”