Dcaf15-mediated EphA2 degradation triggers disruption of the blood-brain barrier during Streptococcus suis meningitis

Disruption of blood-brain barrier (BBB) is the critical step of Streptococcus suis (S. suis) meningitis. Here we show that Ephrin type-A receptor 2 (EphA2) plays an important role in BBB against S. suis meningitis. S. suis downregulates EphA2 and EphA2 deficiency aggravates S. suis-induced BBB disruption in vitro and in vivo. We identify that EphA2-mediated autophagy alleviates S. suis-induced BBB disruption. To destroy the protective effect of EphA2 in BBB, S. suis recruits E3 ligase DCAF15 to interact with EphA2, which induces EphA2 ubiquitination and degradation. Mechanically, DCAF15 promotes K48- and K63-linked ubiquitination of EphA2 at K646, K649 and K754. In addition, S. suis serine/threonine protein kinase (STK) is indispensable for EphA2 degradation. STK phosphorylates histone deacetylase SIRT1 at S48 to trigger the deacetylation of DCAF15, enhancing DCAF15-EphA2 interaction and promoting ubiquitinated degradation of EphA2, thereby disrupting BBB. Moreover, acetylation of DCAF15 at K552 and K581 sites is involved in mediating EphA2 ubiquitination and BBB stability. Our study suggests a protective role of EphA2 in S. suis-induced BBB disruption, which provides a valuable insight on the development of EphA2 as a potential therapeutic target to treat bacterial meningitis.