Kv3.3 Potassium Channels Activate the TBK1 Signaling Pathway

Abstract

Mutations in KCNC3, which encodes the Kv3.3 potassium channel, are linked to degeneration of the cerebellum (SCA13, spinocerebellar ataxia type 13). We found that Kv3.3 channels bind and stimulate Tank Binding Kinase 1 (TBK1), an enzyme that controls trafficking of membrane proteins into multivesicular bodies. TBK1 activity regulates binding of the channel with Hax-1, an anti-apoptotic protein required for survival of cerebellar neurons, and that embeds Kv3.3 in a stable actin cytoskeleton at the plasma membrane. TBK1 activity is elevated several-fold in the cerebellum of animals expressing a SCA13 mutant channel. Cells that express the mutant channel have increased internalization of Hax-1 and accumulate multivesicular bodies containing this cell survival protein, coupled to depolarization-induced loss of the channels themselves. Our studies indicate that the activation of Kv3.3 channels is linked directly to TBK1 activity and channel mutations enhance internalization of the cell survival protein Hax-1 to which they are bound.