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2017-02-10

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cc-by (c) Martínez Mármol, Ramón et al., 2017
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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Recurs relacionat

https://doi.org/10.1038/srep42395

Resum

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.

Matèries

Sistema nerviós, Ubiqüitina

Matèries (anglès)

Nervous system, Ubiquitin

Citació

Col·leccions

Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Citació

MARTÍNEZ MÁRMOL, Ramón, et al. Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein Kinase C-dependent modulation. Scientific Reports. 2017. Vol. 7, num. 42395. ISSN 2045-2322. [consulted: 18 of August of 2026]. Available at: https://hdl.handle.net/2445/120567

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