Exploring the sirtuin functionality in aging through the human protein interaction networks

Abstract

The sirtuin family contains seven proteins with the functions in multiple diseases of aging, which makes them an attractive subject for the development of therapies of age-related diseases and anti-aging treatments. The primary objective of the protein-interaction network analysis presented here is to identify the signaling pathways and protein nodes driving the functions of the sirtuins. For this purpose, the protein-protein interaction data were collected from the available public databases, which fulfilled the quality threshold and included at least one member of the sirtuin family. The databases provided 66 interactions validated by several experiments, which were further processed by the bioinformatic tools connected to the integrated genomic, proteomic, and pharmacologic data. The interactions were analyzed by the pathway enrichment, the gene function prediction analysis, and the protein node prioritization by use of Cytoscape applications GeneMania and Cytohubba. The constructed sirtuin protein interaction network (SPIN) contained after the extension 98 protein nodes. TGFβ, PTK2, CARM1, Notch signaling and the pathways regulating androgen and estrogen levels, significantly scored in the pathway enrichment analysis of SPIN. The enriched signaling pathways mediating the pleiotropic effects of the sirtuin family, play the roles in several age-related diseases probably. The Cytohubba application has highlighted the function of HDAC1, EP300, SMAD4, MYC, SIN3A, RBBP4, HDAC, SIN3B, RBBP7 and SMAD3 as the high priority protein nodes driving the molecular functions of SPIN. The presented protein interaction study provide new understandings of the sirtuin functions in the longevity and diseases of aging including cancer, neurodegenerative and metabolic disorders.