E3 Ubiquitin Ligase RNF125 Activates Interleukin-36 Receptor Signaling and Contributes to Its Turnover
| Autor: | C. Cheng Kao, Siddhartha S. Saha, Gary O. Caviness, Guanghui Yi, Ernest L. Raymond, M. Lamine Mbow |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Endocytic cycle Protein degradation 03 medical and health sciences Ubiquitin Immunology and Allergy Humans Psoriasis RNA Small Interfering Receptor Inflammation biology Chemistry HEK 293 cells Protein turnover Ubiquitination Receptors Interleukin Endocytosis Cell biology Ubiquitin ligase Protein Transport 030104 developmental biology HEK293 Cells Mutation biology.protein Signal transduction Lysosomes Interleukin-18 Receptor alpha Subunit Signal Transduction |
| Zdroj: | Journal of innate immunity. 10(1) |
| ISSN: | 1662-8128 |
| Popis: | Signaling by the interleukin-36 receptor (IL-36R) is linked to inflammatory diseases such as psoriasis. However, the regulation of IL-36R signaling is poorly understood. Activation of IL-36R signaling in cultured cells results in an increased polyubiquitination of the receptor subunit, IL-1Rrp2. Treatment with deubiquitinases shows that the receptor subunit of IL-36R, IL-1Rrp2, is primarily polyubiquitinated at the K63 position, which is associated with endocytic trafficking and signal transduction. A minor amount of ubiquitination is at the K48 position that is associated with protein degradation. A focused siRNA screen identified RNF125, an E3 ubiquitin ligase, to ubiquitinate IL-1Rrp2 upon activation of IL-36R signaling while not affecting the activated IL-1 receptor. Knockdown of RNF125 decreases signal transduction by the IL-36R. Overexpression of RNF125 in HEK293T cells activates IL-36R signaling and increases the ubiquitination of IL-1Rrp2 and its subsequent turnover. RNF125 can coimmunoprecipitate with the IL-36R, and it traffics with IL-1Rrp2 from the cell surface to lysosomes. Mutations of Lys568 and Lys569 in the C-terminal tail of IL-1Rrp2 decrease ubiquitination by RNF125 and increase the steady-state levels of IL-1Rrp2. These results demonstrate that RNF125 has multiple regulatory roles in the signaling, trafficking, and turnover of the IL-36R. |
| Databáze: | OpenAIRE |
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