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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/120567
Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein Kinase C-dependent modulation
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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.
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MARTÍNEZ MÁRMOL, Ramón, STYRCZEWSKA, Katarzyna, PÉREZ VERDAGUER, Mireia, VALLEJO GRACIA, Albert, COMES I BELTRÁN, Núria, SORKIN, Alexander, FELIPE CAMPO, Antonio. Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein Kinase C-dependent modulation. _Scientific Reports_. 2017. Vol. 7, núm. 42395. [consulta: 27 de gener de 2026]. ISSN: 2045-2322. [Disponible a: https://hdl.handle.net/2445/120567]