Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion Ramona Schuster1, Tânia Simões1, Fabian den Brave2, Mafalda Escobar-Henriques1*, 1Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, D - 50931 Cologne, Germany; 2Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany *Corresponding Author
Cdc48/p97, a ubiquitin-selective chaperone, orchestrates the function of E3 ligases and deubiquitylases (DUBs). Here, we identify a new function of Cdc48 in ubiquitin-dependent regulation of mitochondrial dynamics. Due to the pathological relevance of mitochondrial plasticity, understanding the function and regulation of the key players involved is of great importance. Fusion of mitochondria depends on large dynamin-related GTPases, called mitofusins, that assemble on the outer membrane of mitochondria and mediate membrane mixing upon oligomerization. The attachment of the small modifier ubiquitin to mitofusins regulates mitochondrial outer membrane fusion. Moreover, the DUBs Ubp12 and Ubp2 exert opposing effects on mitochondrial fusion and cleave different ubiquitin chains on the yeast mitofusin Fzo1. We demonstrate that Cdc48 integrates the activities of these two DUBs, which are themselves ubiquitylated. First, Cdc48 promotes proteolysis of Ubp12, stabilizing pro-fusion ubiquitylation on Fzo1. Second, loss of Ubp12 stabilizes Ubp2 and thereby facilitates removal of ubiquitin chains on Fzo1 inhibiting fusion. Thus, Cdc48 synergistically regulates the ubiquitylation status of Fzo1, allowing to control the balance between activation or repression of mitochondrial fusion. In conclusion, we unravel a new cascade of ubiquitylation events, comprising Cdc48 and two DUBs, fine-tuning the fusogenic activity of Fzo1.
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