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Salmonella Inhibits Retrograde Trafficking of Mannose-6-Phosphate Receptors and Lysosome Function

Science  16 Nov 2012:
Vol. 338, Issue 6109, pp. 963-967
DOI: 10.1126/science.1227037

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Subversive Salmonella

Salmonella is one of the most intensively studied bacterial pathogens. The Salmonella-containing vacuole (SCV) has a paradoxical lysosome-like composition: On one hand, the SCV membrane is highly enriched in lysosomal membrane glycoproteins and SCVs are accessible to endolysosomal content, but on the other hand, SCV lumen is relatively devoid of lysosomal hydrolytic enzymes that are delivered by the mannose-6-phosphate receptor pathway. McGourty et al. (p. 963) resolve this paradox by showing that the Salmonella effector SifA interferes with the trafficking of mannose-6-phosphate receptors. This causes misrouting and secretion of lysosomal enzymes and reduces the hydrolytic activity of lysosomes. Intracellular growth of Salmonella was reduced in cells with enhanced lysosomal enzyme activity.

Abstract

Salmonella enterica is an intracellular bacterial pathogen that replicates within membrane-bound vacuoles through the action of effector proteins translocated into host cells. Salmonella vacuoles have characteristics of lysosomes but are reduced in hydrolytic enzymes transported by mannose-6-phosphate receptors (MPRs). We found that the effector SifA subverted Rab9-dependent retrograde trafficking of MPRs, thereby attenuating lysosome function. This required binding of SifA to its host cell target SKIP/PLEKHM2. Furthermore, SKIP regulated retrograde trafficking of MPRs in noninfected cells. Translocated SifA formed a stable complex with SKIP and Rab9 in infected cells. Sequestration of Rab9 by SifA-SKIP accounted for the effect of SifA on MPR transport and lysosome function. Growth of Salmonella increased in cells with reduced lysosomal activity and decreased in cells with higher lysosomal activity. These results suggest that Salmonella vacuoles undergo fusion with lysosomes whose potency has been reduced by SifA.

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