Distribution of actin and access of lytic granules at the natural killer cell immunological synapse / Gregory D. Rak.

Rak, Gregory D.
xii, 102 p. : ill. (some col.) ; 29 cm.
Medical subjects:
Cell and Molecular Biology.
Dissertations, Academic.
Local subjects:
Penn dissertations -- Cell and molecular biology.
Cell and molecular biology -- Penn dissertations.
Natural killer cells eliminate susceptible target cells through the directed secretion of the contents of lytic granules. In order to achieve secretion, natural killer cells must form an immunological synapse with the target cell. This synapse is characterized by accumulation of a robust filamentous actin network. Previously this network was shown to resemble a ring with a central clearance through which it was believed lytic granules were delivered, unobstructed, to the plasma membrane. This paradigm was challenged recently by the studies implicating the actin motor protein, myosin IIA, in the secretory process. As myosin IIA was necessary for secretion, it stood to reason that actin was also required. Thus, we reevaluated the synaptic actin network and its relation to lytic granules and secretion using microscopy techniques that provide enhanced sensitivity and resolution compared to those used historically. We find that the filamentous actin network is pervasive and that lytic granules access the plasma membrane in minimally sufficiently sized clearances in the network. We further demonstrate that myosin IIA is not required for appropriate filament architecture at the synapse, but rather functions in facilitating appropriate lytic granule dynamics. Thus, we redefine the paradigm of the distribution of filamentous actin at the immunological synapse, propose a function for actin in mediating granule release, and further our knowledge on the role of myosin IIA in facilitating degranulation. Ultimately, this work advances our understanding of the cell biological process of secretion in the context of the cortical actin network.
Adviser: Jordan S. Orange.
Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2011.
Includes bibliographical references.
Orange, Jordan S., advisor.
University of Pennsylvania.
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