A TBK1 Y105C mutation that reduces IRF3 phosphorylation is associated with familial recurrent myopericarditis, suggesting that inherited susceptibility to viral infections may be an important factor in the pathogenesis of idiopathic recurrent pericarditis.
Key Findings
Results
Whole-exome sequencing of a pedigree with familial recurrent myopericarditis identified a Y105C mutation in TBK1, a kinase that regulates antiviral responses driven by the IRF3 transcription factor.
Three individuals in the pedigree suffered from idiopathic recurrent pericarditis (IRP) presenting with myocardial involvement (myopericarditis).
The Y105C substitution maps at the interface between the kinase and scaffold domain of TBK1.
TBK1 is a kinase that regulates antiviral responses driven by the IRF3 transcription factor.
Results
Molecular modeling predicted a destabilizing effect of the Y105C variant on TBK1 protein structure.
Computational investigation included estimating free-energy changes and undertaking molecular dynamic simulations of wild type and mutant proteins.
The Y105C substitution maps at the interface between the kinase and scaffold domain of TBK1, a structurally important location.
The destabilizing effect predicted by molecular modeling was experimentally validated in over-expression studies.
Results
The TBK1 Y105C mutation caused a significant reduction in IRF3 phosphorylation in overexpression studies.
Wild-type and mutagenized cDNAs were overexpressed in HEK293 cells.
Protein expression and phosphorylation were characterized by western blotting.
The Y105C mutation affected kinase activity, causing a significant reduction in IRF3 phosphorylation.
Results
TBK1 was required for TLR3-IRF3 signaling in primary human pericardial fibroblasts, but TLR3 was weakly expressed in these cells.
Gene expression was measured in primary pericardial fibroblasts using real-time PCR.
TLR3 was found to be weakly expressed in primary human pericardial fibroblasts.
The low expression of TLR3 in pericardial fibroblasts was interpreted as making these cells especially vulnerable to mutations that disrupt TLR3-IRF3 signaling.
Discussion
The findings suggest that inherited susceptibility to viral infections may be an important factor in the pathogenesis of idiopathic recurrent pericarditis.
IRP is increasingly considered an autoinflammatory condition, but pathogenic pathways remain poorly understood.
The disruption of TBK1-mediated IRF3 activation impairs antiviral innate immune responses.
Because pericardial fibroblasts express low levels of TLR3, they may be especially vulnerable to mutations that disrupt TLR3-IRF3 signaling, linking the genetic defect to pericardial tissue-specific disease susceptibility.
What This Means
This research describes a family in which three members developed recurrent inflammation of both the heart muscle and the sac surrounding the heart (myopericarditis). Scientists analyzed the DNA of affected family members using a technique called whole-exome sequencing and found a mutation in a gene called TBK1. This gene encodes a protein that normally helps the body fight off viral infections by activating an immune signaling pathway involving a protein called IRF3. The mutation, called Y105C, sits at a structurally critical location in the TBK1 protein and was shown — both through computer modeling and laboratory experiments — to destabilize the protein and reduce its ability to activate IRF3.
The researchers also discovered that the cells lining the pericardium (the sac around the heart), called pericardial fibroblasts, naturally express very low levels of a viral sensing protein called TLR3, which works upstream of TBK1 in the antiviral signaling chain. This means that pericardial tissue may already have a limited capacity to detect and respond to viral infections, and a mutation that further weakens this pathway could leave the pericardium particularly vulnerable to virus-triggered inflammation.
This research suggests that some cases of recurrent pericarditis that were previously considered to have no known cause may actually result from inherited defects in antiviral immune responses. Rather than being purely an autoimmune or random inflammatory condition, recurrent pericarditis in some families may be driven by a genetically reduced ability to clear viral infections from pericardial tissue. This opens potential new avenues for understanding and eventually treating this condition.
Peet C, Orchard T, Cruz C, Hernandez-Cordero A, Omoyinmi E, Mahil S, et al.. (2026). A TBK1 mutation disrupting IRF3 activation is associated with familial recurrent myopericarditis.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1906965