A AAA ATPase Cdc48 with a cofactor Ubx2 facilitates ubiquitylation of a mitochondrial fusion-promoting factor Fzo1 for proteasomal degradation

Dynamic functionality of mitochondria is maintained by continual fusion and fission events. A mitochondrial outer membrane protein Fzo1 plays a pivotal role upon mitochondrial fusion by homo-oligomerization to tether fusing mitochondria. Fzo1 is tightly regulated by ubiquitylations and the ubiquitin-responsible AAA protein Cdc48. Here, we show that a Cdc48 cofactor Ubx2 facilitates Fzo1 turnover. The Cdc48-Ubx2 complex has been shown to facilitate degradation of ubiquitylated proteins stacked at the protein translocation complex in the mitochondrial outer membrane by releasing them from the translocase. By contrast, in the degradation process of Fzo1, the Cdc48-Ubx2 complex appears to facilitate the degradation-signalling ubiquitylation of the substrate itself. In addition, the Cdc48-Ubx2 complex interacts with Ubp2, a deubiquitylase reversing the degradation-signalling ubiquitylation of Fzo1. These results suggest that the Cdc48-Ubx2 complex regulates Fzo1 turnover by modulating ubiquitylation status of the substrate.