Functional Characterization of UVRAG and ANP32B in Immune Cells Using Gene-deficient Mice

This dissertation is a functional characterization of UVRAG and ANP32B in the immune system using gene deficient mice. Focus 1: UVRAG is a putative tumour suppressor with potential roles in autophagy and endocytic trafficking. Despite a plethora of in vitro data, the in vivo role of this gene remains poorly understood. Here, we report the generation and characterization of the T cell specific UVRAG deficient mice. These mice exhibited normal T cell development but impaired homeostasis in the periphery, rendering them unable to clear LCMV infections. We demonstrate that UVRAG may be dispensable for T cell autophagy but it is required for the homeostatic survival and proliferation of naïve T cells. Taken together, our data provide insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve T cell homeostasis. Focus 2: ANP32B belongs to a highly conserved and broadly expressed family of ANP32 proteins that have been implicated in many cellular functions. Based on previous analyses of mice bearing targeted mutations of Anp32a or Anp32e, there has been speculation that all ANP32 proteins play redundant roles and are dispensable for normal development. Here, we report that ANP32B expression is associated with poor prognosis in human breast cancer. Using ANP32B-deficient mice, we demonstrate a hierarchy of importance for the mammalian Anp32 genes, with Anp32b being the most critical for normal development. In addition, we reveal important roles for ANP32B in differentiation, homeostasis and activation of immune cells. Together, these are novel findings implicating ANP32B in mammalian development and immune cell function.Ph.D.2018-06-13 00:00:0