PI31 Is an Adaptor Protein for Proteasome Transport in Axons and Required for Synaptic Development

Protein degradation by the ubiquitin-proteasome system is critical for neuronal function. Neurons utilize microtubule-dependent molecular motors to allocate proteasomes to synapses, but how proteasomes are coupled to motors and how this is regulated to meet changing demand for protein breakdown remain largely unknown. We show that the conserved proteasome-binding protein PI31 serves as an adaptor to couple proteasomes with dynein light chain proteins (DYNLL1/2). The inactivation of PI31 inhibited proteasome motility in axons and disrupted synaptic proteostasis, structure, and function. Moreover, phosphorylation of PI31 by p38 MAPK enhanced binding to DYNLL1/2 and promoted the directional movement of proteasomes in axons, suggesting a mechanism to regulate loading of proteasomes onto motors. Inactivation of PI31 in mouse neurons attenuated proteasome movement in axons, indicating this process is conserved. Because mutations affecting PI31 activity are associated with human neurodegenerative diseases, impairment of PI31-mediated axonal transport of proteasomes may contribute to these disorders.