Adaptor-mediated interaction between Kv1.3 and Nedd4-2 E3 ubiquitin ligase

The voltage-gated potassium channel Kv1.3 is crucial for immune responses. During proinflammatory stimulation, Kv1.3 is upregulated, enhancing Ca²⁺ signaling and leukocyte activation. To prevent prolonged lymphocyte activity, excess Kv1.3 must be removed from the plasma membrane, as elevated levels are linked to chronic inflammation. The ubiquitin E3 ligase Nedd4-2 is a key negative regulator that promotes Kv1.3 degradation through ubiquitination and lysosomal targeting. Because Kv1.3 lacks canonical PY motifs required for Nedd4-2 binding, adaptor proteins are necessary. Our findings show that Ndfip1 and specific 14-3-3 proteins facilitate the Nedd4-2–Kv1.3 interaction. Following PKC activation, a rapid, transient association between Kv1.3 and Nedd4-2 occurs near the membrane, initiating ubiquitination, vesicular internalization, and lysosomal degradation. This work identifies Nedd4-2 adaptors that mediate Kv1.3 regulation, highlighting Ndfip1 as a key factor while the roles of individual 14-3-3 isoforms remain to be clarified. Kv1.3 upregulation enhances immune activation, but excess channels are removed via Nedd4-2– mediated ubiquitination and lysosomal degradation. Ndfip1 and specific 14-3-3 proteins facilitate this process, with Ndfip1 emerging as a key regulator.