The role of Gamma interferon Inducible Lysosomal Thiol reductase (GILT) in immune and cellular functions
Thesis (Ph.D.)--Georgetown University, 2008.; Includes bibliographical references. Gamma interferon Inducible Lysosomal Thiol reductase (GILT) is an enzyme involved in the initial steps of antigen processing and presentation. GILT facilitates protein unfolding, which makes the endocytosed protein accessible to further enzymatic processing by lysosomal/endosomal proteases. In order to study the in vivo role of GILT, a GILT-/- mouse was previously generated. It has been shown that by changing the redox state of exogenous antigenic proteins, GILT alters the adaptive immune response. Mice lacking GILT have defective immune responses against disulfide bond containing proteins. In order to detect possible alterations in the self-peptide repertoire between GILT wild-type (WT) and deficient mice, we have isolated MHC class II associated peptides from mouse splenocytes and analyzed them by ESI-MS/MS tandem mass spectrometry. We have found an altered self-peptide repertoire in the GILT-deficient cells in comparison to the GILT WT cells. We have also shown that GILT is expressed not only in professional antigen presenting cells, but also in mouse T cells and fibroblasts. Furthermore, we have defined a novel role of GILT in the regulation of cellular proliferation. GILT appears to have an inhibitory role in T cell activation, and in cellular proliferation of fibroblasts. We have identified the mitochondrial manganese superoxide dismutase (SOD2) as one of the key intermediates through which GILT alters cellular proliferation of fibroblasts and T cells. The expression and activity of SOD2 is reduced in the absence of GILT. In addition, forced increase of SOD2 expression in the absence of GILT restores proliferation of mouse fibroblasts to wild type levels. Therefore, GILT appears to have an important role in cellular proliferation, mediated through its effect on SOD2 protein expression and activity.
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THE REGULATORY ROLES OF GAMMA INTERFERON INDUCIBLE LYSOSOMAL THIOL REDUCTASE (GILT) IN CELLULAR REDOX HOMEOSTASIS Chiang, Hao-Sen (Georgetown University, 2011)Redox regulation is critical for a number of cellular functions and has been implicated in the etiology and progression of cardiovascular diseases, neurodegenerative diseases, and cancer. It has been shown that in the ...