The p97-UBXN1 complex regulates aggresome formation
The recognition and disposal of misfolded proteins is essential for the maintenance of cellular homeostasis. Perturbations in the pathways that promote degradation of aberrant proteins contribute to a variety of protein aggregation disorders broadly termed proteinopathies. The p97 AAA-ATPase in combination with adaptor proteins functions to identify ubiquitylated proteins and target them for degradation by the proteasome or autophagy. Mutations in p97 cause multi-system proteinopathies; however, the precise defects underlying these disorders are unclear. Here, we systematically investigate the role of p97 and its adaptors in the process of formation of aggresomes, membrane-less structures containing ubiquitylated proteins that arise upon proteasome inhibition. We demonstrate that p97 mediates aggresome formation and clearance and identify a novel role for the adaptor UBXN1 in the process of aggresome formation. UBXN1 is recruited to aggresomes and UBXN1 knockout cells are unable to form aggresomes. Loss of p97-UBXN1 results in increased Huntingtin polyQ inclusion bodies both in mammalian cells as well as in a C.elegans model of Huntington's Disease. Together our work identifies evolutionarily conserved roles for p97-UBXN1 in the disposal of protein aggregates.