? The post-translational modification of proteins by specific sugar linkages in the Golgi apparatus provides a means to regulate cellular and organisim physiology by altering glycoprotein structure and function. The most studied post-translational modification to protein is intracellular phosphorylation; however similar genetic studies by this laboratory with Golgi glycosyltransferase (GT) and glycosidase (GS) genes have revealed essential biological roles for glycan branches and specific saccharide linkages in embryogenesis, heart development, inflammation, glycoprotein and cell homeostasis, as well as providing a model of the abnormalities occurring in the human genetic disease Congenital Disorder of Glycosylation (CDG) type II-a. Novel unexpected pathways in asparagine- (N) linked and serine/threonine- (O) linked protein glycosylation have also been uncovered. Furthermore, a high occurrence of immune system defects including an autoimmune disease similar to human systemic lupus erythematosus has been observed. These findings may be of significant medical relevance in light of our recent studies revealing that the physiologic functions of complex-type N-glycans are highly conserved between both mouse and human species. The studies proposed herein further these studies and are focused on investigations of how altered protein glycosylation leads to autoimmune disease, and participates in a novel mechanism of B lymphocyte homeostasis among the lymph nodes. The emergence of adult onset SLE in mice lacking alpha-mannosidase (alphaM)-II reflects the varied specifically and expression of the alternate pathway in complex-type N-glycan biosynthesis in development and function in vivo. Further studies to elucidate the identity of the gene encoding the alphaM-III activity, responsible for the alternate pathway in complex N-glycan production, will be approached using mice recently developed by others that lack the alphaM-IIx gene. Proposed studies include analyses of mice lacking both alphaM-II and alphaM-IIx to determine if they recapitulate the loss of Mgat2 gene encoded GlcNAcT-II activity in the mouse model of CDG type IIa. The autoimmune pathogenesis of Mgat2-null mice will be similarly studied as results obtained may be relevant to aging CDG Type IIa patients. These studies should provide further understanding of the role and specific functions of protein glycosylation in physiology and disease. ? ?
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