Type VII secretion system extracellular protein B targets STING to evade host anti-<i>Staphylococcus aureus</i> immunity.

Abstract

<i>Staphylococcus aureus</i> (<i>S. aureus</i>) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, <i>S. aureus</i> type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by <i>S. aureus</i> T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat <i>S. aureus</i> infections.