Study of immune cell signaling modulation by Yersinia protein kinase A (YpkA/YopO).
Sood, Arpana.
2013
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Abstract: Bacterial
pathogens employ several strategies to dampen host cell immune responses. In this work
we studied a secreted effector protein of the Yersinia pseudotuberculosis type-three
secretion system (T3SS). We found that Yersinia protein kinase A (YpkA), employs
serine-kinase activity to target immune cell signaling and dampen chemotaxis and
reactive oxygen species (ROS)-production. ... read moreCell chemotaxis is a fundamental biological
process, and often targeted by pathogens in the context of immunity. YpkA specifically
dampens chemokine receptor signaling to inhibit directional movement, or chemotaxis, of
infected cells. However, YpkA does not prevent cell spread on substrate-coated slides,
indicating that cytoskeletal mechanics remain functional. The goal of this thesis was to
dissect the mechanism by which YpkA inhibits directional cell movement. Chemokine
activation of immune cells requires the functions of several heterotrimeric G proteins.
We found that YpkA dampens signaling mediated by Gαi2 and Gα13, thereby
preventing T cell responses to the chemokine Sdf-1, and inhibiting migration. Moreover,
we determined that YpkA is discriminatory in substrate phosphorylation, as it
phosphorylates Gαq but not Gα13. Both G proteins couple to the chemokine
receptor CXCR4 and have homologous diphosphate-binding regions, indicating that YpkA
demonstrates target specificity in a host cell. Lastly, we studied the role of YpkA in
modulating oxidative burst, and determined that YpkA kinase activity dampens reactive
oxygen species production in macrophages but not neutrophils. This result suggests that
substrate specificity may dictate the cell- type specific functions of YpkA. Together,
this data supports an idea that Yersinia has evolved to modulate specific immune cell
functions, such as chemotaxis and respiratory burst, by employing effector proteins with
diverse enzymatic activities at different stages during
infection.
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Molecular Microbiology.
Advisors: Joan Mecsas, and Ralph Isberg.
Committee: Katya Heldwein, Carol Kumamoto, and James Bliska.
Keywords: Cellular biology, Microbiology, and Molecular biology.read less - ID:
- 3197xz510
- Component ID:
- tufts:20571
- To Cite:
- TARC Citation Guide EndNote
