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 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, Tyr(641). 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.
Ong
Yi-Ching
YC
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
Reese
Michael L
ML
Boothroyd
John C
JC
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014122:Toxoplasma / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D014123:Toxoplasmosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D015800:Protozoan Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D037521:Virulence Factors; D011505:Protein-Tyrosine Kinases; C552524:Rop16 protein, Toxoplasma gondii