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http://hdl.handle.net/2445/120567
Title: | Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein Kinase C-dependent modulation |
Author: | Martínez Mármol, Ramón Styrczewska, Katarzyna Pérez Verdaguer, Mireia Vallejo Gracia, Albert Comes i Beltrán, Núria Sorkin, Alexander Felipe Campo, Antonio |
Keywords: | Sistema nerviós Ubiqüitina Nervous system Ubiquitin |
Issue Date: | 10-Feb-2017 |
Publisher: | Nature Publishing Group |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/srep42395 |
It is part of: | Scientific Reports, 2017, vol. 7, num. 42395 |
URI: | http://hdl.handle.net/2445/120567 |
Related resource: | https://doi.org/10.1038/srep42395 |
ISSN: | 2045-2322 |
Appears in Collections: | Articles publicats en revistes (Institut de Biomedicina (IBUB)) Articles publicats en revistes (Biomedicina) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Bioquímica i Biomedicina Molecular) |
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