regulation of interleukin-10 receptor ubiquitination and stability by beta-trcp-containing ubiquitin e3 ligase白细胞介素- 10u201d受体泛素化调节和稳定beta-trcp-containing e3泛素连接酶.pdfVIP

Regulation of Interleukin-10 Receptor Ubiquitination and Stability by Beta-TrCP-Containing Ubiquitin E3 Ligase 1 1 1 1,2 Hui Jiang , Yi Lu , Liang Yuan , Jianghuai Liu * 1 MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University and National Resource Center for Mutant Mice, Nanjing, China, 2 Zhejiang Key Lab for Technology Application of Model Organisms, School of Life Science, Wenzhou Medical College, Wenzhou, China Abstract Interleukin-10 (IL-10) initiates potent anti-inflammatory effects via activating its cell surface receptor, composed of IL-10R1 and IL-10R2 subunits. The level of IL-10R1 is a major determinant of the cells’ responsiveness to IL-10. Here, via a series of biochemical analyses using 293T cells reconstituted with IL-10R1, we identify the latter as a novel substrate of bTrCP- containing ubiquitin E3 ligase. Within the intracellular tail of IL-10R1, a canonical (318DpSGFGpS) and a slightly deviated (369DpSGICLQEP) bTrCP recognition motif can additively recruit bTrCP in a phosphorylation-dependent manner. bTrCP recruitment leads to ubiquitination, endocytosis and degradation of IL-10R1, subsequently reducing the cellular responsiveness to IL-10. Our study uncovers a novel negative regulatory mechanism that may potentially affect IL-10 function in target cells under physiological or pathological conditions. Citation: Jiang H, Lu Y, Yuan L, Liu J (2011) Regulation of Interleukin-10 Receptor Ubiquitination and Stability by Beta-TrCP-Containing Ubiquitin E3 Ligase. PLoS ONE 6(11): e27464. doi:10.1371/journal.pone.0027464 Editor: Laszlo Buday, Hungarian Academy of Sciences, Hungary Received October 10, 2011; Acce