Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein Kinase C-dependent modulation
| Autor: | Katarzyna Styrczewska, Mireia Pérez-Verdaguer, Alexander Sorkin, Albert Vallejo-Gracia, Ramón Martínez-Mármol, Antonio Felipe, Núria Comes |
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| Přispěvatelé: | Universitat de Barcelona |
| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Nervous system Adenosine Nedd4 Ubiquitin Protein Ligases Endocytic cycle Down-Regulation Endocytosis complex mixtures Article Mice 03 medical and health sciences Membrane Microdomains 0302 clinical medicine Ubiquitin Animals Humans Sistema nerviós Protein Kinase C Protein kinase C Membrane potential Kv1.3 Potassium Channel Multidisciplinary biology Protein Stability HEK 293 cells Ubiquitination Dendritic Cells Macrophage Activation Clathrin Potassium channel Rats Cell biology HEK293 Cells 030104 developmental biology nervous system biology.protein Tetradecanoylphorbol Acetate Lysosomes Ubiqüitina Disks Large Homolog 4 Protein Postsynaptic density 030217 neurology & neurosurgery |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Recercat. Dipósit de la Recerca de Catalunya instname Scientific Reports |
| Popis: | The voltage-dependent potassium channel Kv1.3 plays essential physiological functions in the immune system. Kv1.3, regulating the membrane potential, facilitates downstream Ca2+ -dependent pathways and becomes concentrated in specific membrane microdomains that serve as signaling platforms. Increased and/or delocalized expression of the channel is observed at the onset of several autoimmune diseases. In this work, we show that adenosine (ADO), which is a potent endogenous modulator, stimulates PKC, thereby causing immunosuppression. PKC activation triggers down-regulation of Kv1.3 by inducing a clathrin-mediated endocytic event that targets the channel to lysosomal-degradative compartments. Therefore, the abundance of Kv1.3 at the cell surface decreases, which is clearly compatible with an effective anti-inflammatory response. This mechanism requires ubiquitination of Kv1.3, catalyzed by the E3 ubiquitin-ligase Nedd4-2. Postsynaptic density protein 95 (PSD-95), a member of the MAGUK family, recruits Kv1.3 into lipid-raft microdomains and protects the channel against ubiquitination and endocytosis. Therefore, the Kv1.3/PSD-95 association fine-tunes the anti-inflammatory response in leukocytes. Because Kv1.3 is a promising multi-therapeutic target against human pathologies, our results have physiological relevance. In addition, this work elucidates the ADO-dependent PKC-mediated molecular mechanism that triggers immunomodulation by targeting Kv1.3 in leukocytes. |
| Databáze: | OpenAIRE |
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