PI31 is an adaptor protein for proteasome transport in axons and required for synaptic development and function

Abstract

Degradation of proteins by the ubiquitin-proteasome pathway (UPP) is critical for the maintenance of protein homeostasis, cell function and survival. While all cells require regulated protein degradation, nerve cells face unique challenges as their highly complex structure and large intracellular space requires special mechanisms to allocate proteasomes to appropriate sub-cellular compartments where protein breakdown occurs. Here we show that the conserved proteasome-binding protein PI31 mediates axonal transport of proteasomes. PI31 binds directly to both proteasomes and dynein light chain LC8-type proteins (DYNLL1/2) and thereby promotes the formation of DYNLL1-PI31-proteasome complexes both in vivo and in vitro. Inactivation of PI31 inhibits proteasome motility in axons of Drosophila neurons, similar to ablation of dDYNLL1/ctp, and it disrupts synaptic protein homeostasis, structure and function. These results indicate that PI31 serves a critical function as an adapter protein to transport proteasomes to the periphery of neurons via microtubule-based motors. Because mutations affecting the activity of PI31 are associated with human neurodegenerative diseases, it is possible that impairment of PI31-mediated axonal transport is the root cause of these disorders.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.