Defining In Vivo Functions of the Atypical Ubiquitin Conjugating Enzyme, Ube2W.

[摘要] Ubiquitination is a common post-translational modification that is critically important to many different cellular pathways. Dysfunction of ubiquitin pathways can disrupt various cellular processes that eventually cause diseases such as Huntington’s disease (HD). Unlike typical ubiquitination, which happens at lysine residues of substrates, Ube2W attaches ubiquitin in an atypical manner: to the N- termini of substrates. Disordered N-termini are believed to represent thepreferred substrates for Ube2W. In chapter 1, I review recent studies of typical lysine ubiquitination and atypical ubiquitination, including Ube2W-mediated N- terminal ubiquitination. I also review ubiquitin pathways implicated in HD, since the disordered N-terminus of the disease protein, Huntingtin (Htt), is a compelling candidate substrate for Ube2W and the focus of later studies. I then describe the results of two research projects that investigate Ube2W in vitro and vivo functions. In chapter 2, using mice in which the Ube2W is knocked out, I present evidence that Ube2W is important for early postnatal survival and plays significant roles in in multiple organ systems; I also provide in vivo evidence that supports the view that Ube2W preferentially targets disordered substrates. In chapter 3, using cultured cells and genetic crosses in mouse models, I show that Ube2W regulates the solubility of mutant Htt. Ube2W deficiency significantly increaseslevels of soluble Htt monomers and reduces Htt-mediated neurotoxicity. Chapter 4 concludes the dissertation with thoughts of future studies. Taken together, this dissertation provides in vivo evidence supporting Ube2W’s ability to N-terminally ubiquitinate misfolded proteins, which is key to multiple cellular pathways and organ functions. This dissertation establishes novel insights to the in vivo functions of Ube2W and N-terminal ubiquitination.!

[发布机构] University of Michigan

[效力级别] Ube2W

[关键词] Defining In Vivo Functions of the Atypical Ubiquitin Conjugating Enzyme;Ube2W;Neurosciences;Health Sciences;Neuroscience