Showing papers by "Hermann Steller published in 2018"

PI31 is an adaptor protein for proteasome transport in axons

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.

PI31 is an adaptor protein for proteasome transport

Abstract: 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.