Abstract
Cell stress and infection promote the formation of ubiquitinated aggregates in both non-immune and immune cells. These structures are recognised by the autophagy receptor p62/sequestosome 1 and are substrates for selective autophagy. The intracellular growth of Salmonella enterica occurs in a membranous compartment, the Salmonella-containing vacuole (SCV), and is dependent on effectors translocated to the host cytoplasm by the Salmonella pathogenicity island-2 (SPI-2) encoded type III secretion system (T3SS). Here, we show that bacterial replication is accompanied by the formation of ubiquitinated structures in infected cells. Analysis of bacterial strains carrying mutations in genes encoding SPI-2 T3SS effectors revealed that in epithelial cells, formation of these ubiquitinated structures is dependent on SPI-2 T3SS effector translocation, but is counteracted by the SPI-2 T3SS deubiquitinase SseL. In macrophages, both SPI-2 T3SS-dependent aggregates and aggresome-like induced structures (ALIS) are deubiquitinated by SseL. In the absence of SseL activity, ubiquitinated structures are recognized by the autophagy receptor p62, which recruits LC3 and targets them for autophagic degradation. We found that SseL activity lowers autophagic flux and favours intracellular Salmonella replication. Our data therefore show that there is a host selective autophagy response to intracellular Salmonella infection, which is counteracted by the deubiquitinase SseL.
Highlights
Salmonella enterica is a facultative intracellular pathogen that survives and replicates in a variety of hosts
We have found that intracellular Salmonella induces the formation of ubiquitinated aggregates near the Salmonella-containing vacuole and that these aggregates are recognised by the autophagy machinery
We show that SseL alone can deubiquitinate known substrates that are degraded by autophagy, that it reduces autophagy in infected cells and that its activity can increase intracellular Salmonella replication
Summary
Salmonella enterica is a facultative intracellular pathogen that survives and replicates in a variety of hosts. Intracellular replication occurs in a membraneenclosed compartment, the Salmonella-containing vacuole (SCV), and requires the delivery of an extensive repertoire of effectors to the host cytoplasm by the SPI-2 T3SS [4]. The ability to manipulate the ubiquitin system is a feature common to many intracellular pathogens, including Salmonella, which delivers several effectors to the cell cytosol that interfere with the host cell ubiquitination [5,6]. Absence of the SPI-2 T3SS-delivered deubiquitinase SseL leads to an accumulation of ubiquitinated proteins within infected cells and attenuates Salmonella virulence in mice [7]
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