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Thesis Name： Phosphorylation and Specific Ubiquitin Acceptor Sites Are Required for Ubiquitination and Degradation of the IFNAR1 Subunit of Type I Interferon Receptor Usage： protein synthesis Keyword： Phosphorylation and Specific Ubiquitin Acceptor Sites Are Required for Ubiquitination and Degradatio Remarks： Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCF-Trcp (Skp1-Cullin1-F-box protein transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. In addition, stability of IFNAR1 is regulated by its binding to Tyk2 kinase. Here we characterize the determinants of IFNAR1 ubiquitination and degradation. We found that the integrity of two Ser residues at positions 535 and 539 within the specific destruction motif present in the cytoplasmic tail of IFNAR1 is essential for the ability of IFNAR1 to recruit -Trcp as well as to undergo efficient ubiquitination and degradation. Using an antibody that specifically recognizes IFNAR1 phosphorylated on Ser535 we found that IFNAR1 is phosphorylated on this residue in cells. This phosphorylation is promoted by treatment of cells with IFN. Although the cytoplasmic tail of IFNAR1 contains seven Lys residues that could function as potential ubiquitin acceptor sites, we found that only three (Lys501, Lys525, and Lys526), all located proximal to the destruction motif, are essential for ubiquitination and degradation of IFNAR1. Expression of Tyk2 stabilized IFNAR1 in a manner that was dependent neither on its binding to -Trcp nor IFNAR1 ubiquitination. We discuss the complexities and specifics of the ubiquitination and degradation of IFNAR1, which is a -Trcp substrate that undergoes degradation via a lysosomal pathway. Original file： No File

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