title: The Salmonella effector SptP dephosphorylates host AAA+ ATPase VCP to promote development of its intracellular replicative niche.
abstract: Virulence effectors delivered into intestinal epithelial cells by Salmonella trigger actin remodeling to direct pathogen internalization and intracellular replication in Salmonella-containing vacuoles (SCVs). One such effector, SptP, functions early during pathogen entry to deactivate Rho GTPases and reverse pathogen-induced cytoskeletal changes following uptake. SptP also harbors a C-terminal protein tyrosine phosphatase (PTPase) domain with no clear host substrates. Investigating SptP's longevity in infected cells, we uncover a late function of SptP, showing that it associates with SCVs, and its PTPase activity increases pathogen replication. Direct SptP binding and specific dephosphorylation of the AAA+ ATPase valosin-containing protein (VCP/p97), a facilitator of cellular membrane fusion and protein degradation, enhanced pathogen replication in SCVs. VCP and its adaptors p47 and Ufd1 were necessary for generating Salmonella-induced filaments on SCVs, a membrane fusion event characteristic of the pathogen replicative phase. Thus, Salmonella regulates the biogenesis of an intracellular niche through SptP-mediated dephosphorylation of VCP.
authors.affiliation: Cambridge University Department of Pathology, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Humphreys
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hume
authors.forename: Vassilis
authors.initials: V
authors.lastname: Koronakis
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D012475:Salmonella / Q000254:growth & development / Q000472:pathogenicity / Q000502:physiology*; D014617:Vacuoles / Q000737:chemistry / Q000382:microbiology; D000074405:Valosin Containing Protein; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001426:Bacterial Proteins; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C491497:UFD1 protein, human; D037521:Virulence Factors; D017027:Protein Tyrosine Phosphatases; C439890:sptP protein, Salmonella typhimurium; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein