PKC Activation Induces Ubiquitination-Dependent KV1.3 Endocytosis Mediated by Nedd4-2 Ubiquitin Ligase

Abstract

The voltage-dependent potassium channel Kv1.3 participates in the immune system physiology. Kv1.3 regulates the membrane potential triggering downstream Ca 2þ -dependent pathways. This channel concentrates in specific membrane microdomains serving as signaling platforms. Altered expression of Kv1.3 is observed at the onset of several autoimmune diseases. We show that adenosine (ADO), acting as a potent endogenous modulator, stimulates PKC, thereby causing immunosuppression. PKC activation down-regulates Kv1.3 triggering a clathrin-mediated internalization that targets the channel to lysosomes. Thus, the amount of Kv1.3 at the plasma membrane decreases, which is clearly compatible with an effective anti-inflammatory response. This mechanism involves ubiquitination of Kv1.3, catalyzed by the E3 ubiquitin-ligase Nedd4-2. Postsynaptic density protein 95 (PSD-95), member of the MAGUK family, situates Kv1.3 into lipid-raft microdomains impairing the ubiquitination and endocytosis of the channel. Therefore, the association of PSD-95 with Kv1.3 would modulate the anti-inflammatory response in leukocytes. This work elucidates the PKC-dependent molecular mechanisms that target Kv1.3 during immunomodulation in leukocytes.