Abstract
Bacterial autophagy—a type of macroautophagy that is also termed xenophagy—selectively targets intracellular bacteria such as group A Streptococcus (GAS), a ubiquitous pathogen that causes numerous serious diseases, including pharyngitis, skin infections, and invasive life-threatening infections. Although bacterial autophagy is known to eliminate invading bacteria via the action of autophagy receptors, the underlying mechanism remains unclear. Herein, we elucidated that Tollip functions as a bacterial-autophagy receptor in addition to participating involved in the intracellular immunity mechanism that defends against bacterial infection. Tollip was recruited to GAS-containing endosomal vacuoles prior to the escape of GAS into the cytosol; additionally, Tollip knockout disrupted the recruitment of other autophagy receptors, such as NBR1, TAX1BP1, and NDP52, to GAS-containing autophagosomes and led to prolonged intracellular survival of GAS. Furthermore, Tollip was found to be required for the recruitment of galectin-1 and -7 to GAS-containing autophagosomes, and immunoprecipitation results indicated that Tollip interacts with galectin-7. Lastly, our data also revealed that galectin-1 and -7 are involved in the restriction of GAS replication in cells. These results demonstrated that Tollip modulates bacterial autophagy by recruiting other autophagy receptors and galectins.
Highlights
Autophagy is a highly conserved intracellular metabolism mechanism in which autophagosome -lysosome fusion facilitates the clearance of intracellular components such as protein aggregates, damaged organelles, and invading pathogens (Ohsumi, 2013)
To determine whether Tollip is involved in the xenophagy triggered in response to bacterial infection, we first evaluated the localization of Tollip in group A Streptococcus (GAS)-infected HeLa cells
Because Tollip mediates the recruitment of autophagy receptors to protein aggregates during aggrephagy (Lu et al, 2014), we investigated whether the recruitment of autophagy receptors to GAS-containing vacuoles is impaired in Tollip-knockout cells
Summary
Autophagy is a highly conserved intracellular metabolism mechanism in which autophagosome -lysosome fusion facilitates the clearance of intracellular components such as protein aggregates, damaged organelles, and invading pathogens (Ohsumi, 2013). Termed xenophagy, targets intracellular pathogens such as bacteria and viruses for clearance through the fusion of pathogen-containing autophagosomes with lysosomes (Nakagawa et al, 2004; Moy et al, 2014). The selective autophagy of pathogens in the cytoplasm is mediated by autophagy receptors that connect their targets to autophagic membranes. It has been reported previously that autophagy functions as a crucial intracellular immune mechanism in the defense against GAS invasion (Nakagawa et al, 2004; Tumbarello et al, 2015; Franco et al, 2017)
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