期刊
CELLULAR SIGNALLING
卷 23, 期 1, 页码 161-170出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2010.08.016
关键词
R2 MEF; Clathrin; Endocytosis; Protein degradation; Lysosome; CD120b
类别
资金
- EC [LSHM-CT-2005-018637]
- Deutsche Forschungsgemeinschaft [KR 3307/1]
Endocytosis is an important mechanism to regulate tumor necrosis factor (TNF) signaling. In contrast to TNF receptor 1 (TNFR1; CD120a), the relevance of receptor internalization for signaling as well as the fate and route of internalized TNF receptor 2 (MHO; CD120b) is poorly understood. To analyze the dynamics of TNFR2 signaling and turnover at the plasma membrane we established a human TNFR2 expressing mouse embryonic fibroblast cell line in a TNFR1(-/-) /TNFR2(-/-) background. TNF stimulation resulted in a decrease of constitutive TNFR2 ectodomain shedding. We hypothesized that reduced ectodomain release is a result of TNF/TNFR2 complex internalization. Indeed, we could demonstrate that TNFR2 was internalized together with its ligand and cytoplasmic binding partners. Upon endocytosis the TNFR2 signaling complex colocalized with late endosome/lysosome marker Rab7 and entered the lysosomal degradation pathway. Furthermore, we identified a di-leucin motif in the cytoplasmic part of TNFR2 suggesting clathrin-dependent internalization of TNFR2. Internalization defective TNFR2 mutants are capable to signal, i.e. activate NF kappa B, demonstrating that the di-leucin motif dependent internalization is dispensable for this response. We therefore propose that receptor internalization primarily serves as a negative feed-back to limit TNF responses via TNFR2. (C) 2010 Elsevier Inc. All rights reserved.
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