Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein kinase C-dependent modulation

• DOI: 10.1038/srep42395
• Publication Date: 2017-02-10T10:13:29Z
• Authors: Ramón Martínez-Má...; Katarzyna Styrcze...; Mireia Pérez-Verd...; Albert Vallejo-Gr...; Núria Comes; Alexander Sorkin; Antonio Felipe
• Keywords: Lipid raft; NEDD4

Abstract The voltage-dependent potassium channel Kv1.3 plays essential physiological functions in the immune system. Kv1.3, regulating membrane potential, facilitates downstream Ca 2+ -dependent pathways and becomes concentrated specific microdomains that serve as signaling platforms. Increased and/or delocalized expression of is observed at onset several autoimmune diseases. In this work, we show adenosine (ADO), which a potent endogenous modulator, stimulates PKC, thereby causing immunosuppression. PKC activation triggers down-regulation by inducing clathrin-mediated endocytic event targets to lysosomal-degradative compartments. Therefore, abundance cell surface decreases, clearly compatible with an effective anti-inflammatory response. This mechanism requires ubiquitination catalyzed E3 ubiquitin-ligase Nedd4-2. Postsynaptic density protein 95 (PSD-95), member MAGUK family, recruits into lipid-raft protects against endocytosis. Kv1.3/PSD-95 association fine-tunes response leukocytes. Because promising multi-therapeutic target human pathologies, our results have relevance. addition, work elucidates ADO-dependent PKC-mediated molecular immunomodulation targeting