The adaptor protein ankyrin-B (AnkB) promotes the axonal transport of multiple organelles by linking the dynein motor accessory factor dynactin to membrane phospholipids, Lorenzo et al. reveal.
Ankyrin proteins are best known for their role in assembling spectrin–actin networks at the plasma membrane. Mice lacking AnkB develop severe brain abnormalities, but the reason for these defects is unclear. Lorenzo et al. found that AnkB-deficient neurons grew shorter axons than wild-type neurons, even though their axonal spectrin networks remained intact.
Instead, the researchers found, knocking out AnkB impaired axonal growth by inhibiting the transport of various organelles along axonal microtubules. Synaptic vesicles, mitochondria, endosomes, and lysosomes all showed reduced motility in the absence of AnkB, particularly in the retrograde direction toward the cell body. AnkB localized to all of these organelles by binding to the phospholipid PI(3)P. Knocking out the PI(3)P-generating kinase PIK3C3 inhibited both AnkB localization and organelle transport.
Retrograde axonal transport is driven by the dynein–dynactin motor complex, and AnkB promotes the formation of skeletal muscle costameres by binding to the dynactin subunit p62. Lorenzo et al. therefore wondered whether AnkB recruits dynactin to axonal cargoes and found that the motor complex was lost from organelles in AnkB-deficient neurons. Moreover, an AnkB mutant unable to bind p62 failed to restore organelle transport and axonal growth.
Mutations in the gene encoding AnkB—including ones affecting a large, axon-specific isoform of the protein—have recently been linked to autism. Senior author Vann Bennett is now interested in investigating whether any of these mutations affect axonal transport.
Text by Ben Short