The allele frequency (AF all) of pSNVs was studied to evaluate the extent of predicted changes in infection-responsive signaling networks in the 16 human populations derived from the gnomAD dataset.
The top proteins with motif-switching pSNVs included transcriptional regulators BCLAF1 and RREB1 and the nuclear matrix protein NUMA. Sixty pSNVs caused motif switches, whereas 37 pSNVs displayed motif-switching impact. The researchers also studied 217 pSNVs with 3,360 motif-rewiring predictions covering 64 kinase families. It was found that the kinase-substrate interactions were limited to phosphosites with at least one pSNV.
The results of the current study demonstrated that hundreds of pSNVs are capable of altering SARS-CoV-2-driven signaling in host cells through kinase sequence motifs. These analyses helped highlight the genetic factors contributing to the variation in SARS-CoV-2 infection and suggest pointers for future translational and mechanistic studies. The authors of this review posted on the medRxiv* preprint server employed an array of methods including functional enrichment analysis, PPI network analysis, and analysis of population frequency and disease annotations of pSNVs. TBK1 is actively involved in innate immune responses and motif switching of pSNVs indicates consistent rewiring of infection signaling networks. These variants disrupt cyclin-dependent kinases (CDK) and mitogen-associated kinase (MAPK) substrate motifs and replace these with motifs recognized by the Tank Binding Kinase 1 (TBK1) of the IKB kinase (IKK) family, referred to as motif switching. In fact, pSNVs are also found in core host processes of the viral life cycle, such as ribonucleic acid (RNA) splicing and interferon (IFN) responses, as well as signaling pathways such as glucose homeostasis pathway associated with COVID-19 co-morbidities, and in other human genes involved in viral infections.Īdditionally, pSNVs induce structural changes in kinase signaling networks and cross-talk of mitogenic and immune response pathways in some populations. This demonstrated the evolution of signaling networks regulating host immune defenses.Īlmost all the viral life cycle processes and host responses involve proteins with pSNVs or specifically motif-rewiring pSNVs. To this end, they found a total of 2,033 infrequent phosphorylation-associated SNVs (pSNVs) with abundant sequence motif alterations. Image Credit: Naty.M / Study designĪ team of researchers recently studied human single nucleotide variants (SNVs) using machine learning to identify amino acid changes that alter kinase-bound sequence motifs. Study: Human phospho-signaling networks of SARS-CoV-2 infection are rewired by population genetic variants. While the genetic variations in humans may impact SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) pathology, their role in the signaling networks remains uncharacterized. When the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects a human host, it takes control of the host’s signaling pathways by inducing protein-protein interactions (PPIs) between host and viral proteins. By Neha Mathur Reviewed by Benedette Cuffari, M.Sc.