PI31 is an adaptor protein for proteasome transport

Protein degradation by the ubiquitin-proteasome system (UPS) is critical for neuronal function, plasticity and survival. Neurons rely on axonal transport of proteasomes to mediate protein breakdown at synapses, but how proteasomes are coupled with molecular motors and how this transport is regulated remains largely unknown. We show that the conserved proteasome-binding protein PI31 mediates axonal transport of proteasomes. PI31 directly interacts with both proteasomes and dynein light chain proteins (DYNLL1/2) and thereby serves as an adaptor to couple proteasomes with motors. Moreover, phosphorylation of PI31 at a conserved site by p38 MAPK promotes binding of PI31 to DYNLL1/2, suggesting a mechanism to regulate loading of proteasomes onto DYNLL1/2. Consistent with this model, both knockout and non-phosphorable mutants of PI31 impair proteasome movement in axons of Drosophila motor neurons. Because mutations affecting PI31 activity are associated with human neurodegenerative diseases, impairment of PI31-mediated axonal transport of proteasomes may be the root cause of these disorders.