S-acylation-dependent membrane microdomain localization of the regulatory Kvβ2.1 subunit

The voltage-dependent potassium (Kv) channel Kv beta family was the first identified group of modulators of Kv channels. Kv beta regulation of the alpha-subunits, in addition to their aldoketoreductase activity, has been under extensive study. However, scarce information about their specific alpha-subunit-independent biology is available. The expression of Kv beta s is ubiquitous and, similar to Kv channels, is tightly regulated in leukocytes. Although Kv beta subunits exhibit cytosolic distribution, spatial localization, in close contact with plasma membrane Kv channels, is crucial for a proper immune response. Therefore, Kv beta 2.1 is located near cell surface Kv1.3 channels within the immunological synapse during lymphocyte activation. The objective of this study was to analyze the structural elements that participate in the cellular distribution of Kv beta s. It was demonstrated that Kv beta peptides, in addition to the cytoplasmic pattern, targeted the cell surface in the absence of Kv channels. Furthermore, Kv beta 2.1, but not Kv beta 1.1, targeted lipid raft microdomains in an S-acylation-dependent manner, which was concomitant with peptide localization within the immunological synapse. A pair of C-terminal cysteines (C301/C311) was mostly responsible for the specific palmitoylation of Kv beta 2.1. Several insults altered Kv beta 2.1 membrane localization. Therefore, growth factor-dependent proliferation enhanced surface targeting, whereas PKC activation impaired lipid raft expression. However, PSD95 stabilized Kv beta 2.1 in these domains. This data shed light on the molecular mechanism by which Kv beta 2.1 clusters into immunological synapses during leukocyte activation.

Automated summary

The Kv beta family is a group of modulators that regulate Kv channels, with Kv beta 2.1 clustering into immunological synapses during leukocyte activation. The localization of Kv beta 2.1 is mainly affected by S-acylation and a pair of C-terminal cysteines, and its targeting to lipid raft microdomains is influenced by various stimuli.