Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

The obligate intracellular parasite, Toxoplasma gondii, modulates host immunity in a variety of highly specific ways. Previous work revealed a polymorphic, injected parasite factor, ROP16, to be a key virulence determinant and regulator of host cell transcription. These properties were shown to be p...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-09, Vol.285 (37), p.28731-28740
Main Authors: Ong, Yi-Ching, Reese, Michael L., Boothroyd, John C.
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Humans
Immunology
Mice
Mice, Knockout
Microbiology
Parasitology
Phosphorylation - genetics
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Protozoan Proteins - genetics
Protozoan Proteins - metabolism
Signal Transduction
STAT Transcription Factor
STAT3 Transcription Factor - genetics
STAT3 Transcription Factor - metabolism
STAT6
STAT6 Transcription Factor - genetics
STAT6 Transcription Factor - metabolism
Toxoplasma - enzymology
Toxoplasma - genetics
Toxoplasma - pathogenicity
Toxoplasma gondii
Toxoplasmosis - enzymology
Toxoplasmosis - genetics
Toxoplasmosis - pathology
Tyrosine Protein Kinase (Tyrosine Kinase)
Virulence Factors - genetics
Virulence Factors - metabolism
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Summary:The obligate intracellular parasite, Toxoplasma gondii, modulates host immunity in a variety of highly specific ways. Previous work revealed a polymorphic, injected parasite factor, ROP16, to be a key virulence determinant and regulator of host cell transcription. These properties were shown to be partially mediated by dysregulation of the host transcription factors STAT3 and STAT6, but the molecular mechanisms underlying this phenotype were unclear. Here, we use a Type I Toxoplasma strain deficient in ROP16 to show that ROP16 induces not only sustained activation but also an extremely rapid (within 1 min) initial activation of STAT6. Using recombinant wild-type and kinase-deficient ROP16, we demonstrate in vitro that ROP16 has intrinsic tyrosine kinase activity and is capable of directly phosphorylating the key tyrosine residue for STAT6 activation, Tyr641. Furthermore, ROP16 co-immunoprecipitates with STAT6 from infected cells. Taken together, these data strongly suggest that STAT6 is a direct substrate for ROP16 in vivo.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.112359