How Fragile We Are: Influence of Stimulator of Interferon Genes (STING) Variants on Pathogen Recognition and Immune Response Efficiency

The
stimulator of interferon genes (STING) protein is a cornerstone
of the human immune response. Its activation by cGAMP in the presence
of cytosolic DNA stimulates the production of type I interferons and
inflammatory cytokines. In the human population, several STING variants
exist and exhibit dramatic differences in their activity, impacting
the efficiency of the host defense against infections. Understanding
the molecular mechanisms of these variants opens perspectives for
personalized medicine treatments against diseases such as viral infections,
cancers, or autoinflammatory diseases. Through microsecond-scale molecular
modeling simulations, contact analyses, and machine learning techniques,
we reveal the dynamic behavior of four STING variants (wild type,
G230A, R293Q, and G230A/R293Q) and rationalize the variability of
efficiency observed experimentally. Our results show that the decrease
in STING activity is linked to a stiffening of key structural elements
of the binding cavity together with changes in the interaction patterns
within the protein.