Abstract
SARS-CoV-2 infection hijacks signaling pathways and induces protein-protein interactions between human and viral proteins. Human genetic variation may impact SARS-CoV-2 infection and COVID-19 pathology; however, the genetic variation in these signaling networks remains uncharacterized. Here, we studied human missense single nucleotide variants (SNVs) altering phosphorylation sites modulated by SARS-CoV-2 infection, using machine learning to identify amino acid substitutions altering kinase-bound sequence motifs. We found 2,033 infrequent phosphorylation-associated SNVs (pSNVs) that are enriched in sequence motif alterations, potentially reflecting the evolution of signaling networks regulating host defenses. Proteins with pSNVs are involved in viral life cycle and host responses, including RNA splicing, interferon response (TRIM28), and glucose homeostasis (TBC1D4) with potential associations with COVID-19 comorbidities. pSNVs disrupt CDK and MAPK substrate motifs and replace these with motifs of Tank Binding Kinase 1 (TBK1) involved in innate immune responses, indicating consistent rewiring of signaling networks. Several pSNVs associate with severe COVID-19 and hospitalization (STARD13, ARFGEF2). Our analysis highlights potential genetic factors contributing to inter-individual variation of SARS-CoV-2 infection and COVID-19 and suggests leads for mechanistic and translational studies.
【초록키워드】 COVID-19, Evolution, SARS-CoV-2, pathology, severe COVID-19, Hospitalization, SARS-COV-2 infection, Human, Genetic, Infection, Comorbidities, interferon, Viral proteins, Viral, immune responses, Genetic variation, RNA splicing, signaling pathway, SNV, signaling pathways, interferon response, protein-protein interaction, homeostasis, Glucose, Single nucleotide variant, association, Amino acid, Signaling, nucleotide, Analysis, MAPK, Pathways, motifs, Missense, amino acid substitutions, host responses, leads, genetic factors, life cycle, host defenses, Factor, TBK1, sequence, viral life cycle, COVID-19 pathology, innate immune responses, motif, SNVs, human genetic variation, kinase, Inter-individual variation, phosphorylation sites, Sequence motifs, amino acid substitution, Host, TRIM28, highlight, ARFGEF2, STARD13, TANK, TBC1D4, identify, involved, in viral, induce, contributing to, translational, disrupt, modulated, alterations, phosphorylation site, with COVID-19, 【제목키워드】 Human, Genetic variant,