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Salmonella inhibits retrograde trafficking of mannose-6-phosphate receptors and lysosome function

Kieran McGourty1, Teresa L Thurston, Sophie A Matthews

  • 1Section of Microbiology, Centre for Molecular Microbiology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.

Science (New York, N.Y.)
|November 20, 2012
PubMed

Insights

Salmonella enterica uses the effector SifA to disrupt host cell lysosome function by interfering with mannose-6-phosphate receptor (MPR) trafficking. This bacterial strategy enhances Salmonella growth by reducing lysosomal activity.

Area of Science:

  • Microbiology
  • Cell Biology
  • Pathogen-Host Interactions

Background:

  • Salmonella enterica is an intracellular pathogen that replicates within vacuoles.
  • Salmonella vacuoles exhibit lysosomal characteristics but have reduced hydrolytic enzyme content.
  • Mannose-6-phosphate receptors (MPRs) are crucial for lysosomal enzyme transport.

Purpose of the Study:

  • To investigate the mechanism by which Salmonella effector SifA affects host cell lysosome function.
  • To determine the role of SifA-SKIP/PLEKHM2 interaction in MPR trafficking.
  • To elucidate how Salmonella manipulates host cell transport pathways for replication.

Main Methods:

  • Investigated the interaction between Salmonella effector SifA and host cell protein SKIP/PLEKHM2.
  • Analyzed the effect of SifA on Rab9-dependent retrograde trafficking of MPRs.
  • Assessed Salmonella growth in host cells with modulated lysosomal activity.

Main Results:

  • SifA binds to SKIP/PLEKHM2, subverting Rab9-dependent MPR retrograde trafficking and attenuating lysosome function.
  • SifA forms a stable complex with SKIP and Rab9 in infected cells, sequestering Rab9.
  • Salmonella growth is enhanced in cells with reduced lysosomal activity and decreased in cells with higher activity.

Conclusions:

  • Salmonella vacuoles fuse with host cell lysosomes whose potency is reduced by SifA.
  • SifA-mediated disruption of MPR trafficking is a key mechanism for Salmonella pathogenesis.
  • Targeting host cell retrograde transport is a conserved bacterial strategy for intracellular replication.

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