Bcl-xL regulates xenophagy by inhibiting the autophagosome-lysosome fusion and bacterial internalization through the Beclin 1-UVRAG complex

Abstract

Starvation-induced autophagy is regulated by a directly interaction between anti-apoptotic proteins Bcl-2/Bcl-xL and autophagy-related protein Beclin 1. Beclin 1 is also considered to involve in multiple vesicle trafficking pathways such as autophagosome elongation and endocytosis by binding to Atg14L and UVRAG. However, precise roles of Bcl-2/Bcl-xL-Beclin 1 complex in anti-bacterial autophagy (xenophagy) are poorly understood. Recently, we reported that Bcl-xL but not Bcl-2 regulates xenophagy using Group A Streptococcus (GAS; Streptococcus pyogenes ) infection model. Knockout of Bcl-xL promoted autophagosome-lysosome fusion and the GAS internalization to host cells. Additionally, knockout of Beclin 1 significantly decreased the GAS internalization. Furthermore, UVRAG interacts with Bcl-xL during GAS infection, and overexpression of UVRAG partially rescued the GAS internalization defect of Beclin 1 knockout (KO) cells. Taken together, our study demonstrates new functions of Bcl-xL in xenophagy as a directly suppresser of autophagosome-lysosome fusion and an indirectly suppresser of GAS internalization via interaction with Beclin 1-UVRAG.