Kv1.3 palmitoylation regulates spatial distribution and channel removal from the immunological synapse.

Kv1.3 is the main voltage-gated potassium channel in T cells. At the immunological synapse (IS), it sustains Ca2⁺ signaling and facilitates T cell activation. Aberrant Kv1.3 expression or activity is linked to autoimmune disorders, yet the mechanisms regulating its targeting and organization at the IS remain unclear. We show that Kv1.3 palmitoylation is a dynamic process mediating channel rearrangement at the IS. The ZDHHC21 acyltransferase, which also S-acylates the TCR, palmitoylates Kv1.3, positioning this enzyme as a potential therapeutic target. Palmitoylation promotes channel migration to the synapse center for removal from the surface. A nonpalmitoylated mutant (Cysless Kv1.3) accumulated at the distal IS and was excluded from lipid raft–enriched domains. Mislocalization and reduced current hindered lymphocyte activation. Moreover, Cysless Kv1.3 showed stronger interaction with PSD95 and cortactin, stabilizing the channel at the surface. These findings highlight S-palmitoylation as a crucial regulator of Kv1.3 during immune responses and a promising target in autoimmune disease therapy.