When proteasomal degradation is impaired, polyubiquitylated proteins are instead transported along microtubules to aggresomes – pericentriolar protein aggregates that store proteins for later removal. Transport to aggresomes is mediated by the cytosolic deacetylase HDAC6, which links polyubiquitin to the microtubule motor dynein. Now, Marcus Groettrup and colleagues () show that the ubiquitin-like protein FAT10, which usually targets proteins for proteasomal degradation, also acts in the aggresome pathway. Using a yeast two-hybrid screen, the authors show that FAT10 interacts with HDAC6; in cells, this only occurs when the proteasome is inhibited. They next identify the domains of each protein that mediate the HDAC6-FAT10 interaction, and go on to show that FAT10 and GFP-FAT10 both localise to aggresomes when a proteasome inhibitor is added; notably, this localisation requires an intact microtubule network. In Hdac6–/– cells treated with a proteasome inhibitor, FAT10- and ubiquitin-containing aggresomes are smaller and less numerous than in wild-type cells. The authors conclude that FAT10 reroutes its target proteins to the aggresome when proteasomal degradation cannot take place. These results enhance our understanding of the diverse cellular strategies for protein degradation.
