title: Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein kinase C-dependent modulation.
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.
authors.affiliation: Molecular Physiology laboratory, Departament de Bioquímica i Biomedicna Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.|Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Ramón
authors.initials: R
authors.lastname: Martínez-Mármol
authors.affiliation: Molecular Physiology laboratory, Departament de Bioquímica i Biomedicna Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Styrczewska
authors.affiliation: Molecular Physiology laboratory, Departament de Bioquímica i Biomedicna Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Pérez-Verdaguer
authors.affiliation: Molecular Physiology laboratory, Departament de Bioquímica i Biomedicna Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Vallejo-Gracia
authors.affiliation: Molecular Physiology laboratory, Departament de Bioquímica i Biomedicna Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.|Laboratory of Neurophysiology, Universitat de Barcelona and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Comes
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sorkin
authors.affiliation: Molecular Physiology laboratory, Departament de Bioquímica i Biomedicna Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Felipe
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D002966:Clathrin / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D002966:Clathrin; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D051664:Kv1.3 Potassium Channel; D008070:Lipopolysaccharides; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D011493:Protein Kinase C; D000241:Adenosine; D013755:Tetradecanoylphorbol Acetate