title: Two deubiquitylases act on mitofusin and regulate mitochondrial fusion along independent pathways.
abstract: Mitofusins, conserved dynamin-related GTPases in the mitochondrial outer membrane, mediate the fusion of mitochondria. Here, we demonstrate that the activity of the mitofusin Fzo1 is regulated by sequential ubiquitylation at conserved lysine residues and by the deubiquitylases Ubp2 and Ubp12. Ubp2 and Ubp12 recognize distinct ubiquitin chains on Fzo1 that have opposing effects on mitochondrial fusion. Ubp2 removes ubiquitin chains that initiate proteolysis of Fzo1 and inhibit fusion. Ubp12 recognizes ubiquitin chains that stabilize Fzo1 and promote mitochondrial fusion. Self-assembly of dynamin-related GTPases is critical for their function. Ubp12 deubiquitylates Fzo1 only after oligomerization. Moreover, ubiquitylation at one monomer activates ubiquitin chain formation on another monomer. Thus, regulation of mitochondrial fusion involves ubiquitylation of mitofusin at distinct lysine residues, intermolecular crosstalk between mitofusin monomers, and two deubiquitylases that act as regulatory and quality control enzymes.
authors: Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors: Fabian
authors: F
authors: Anton
authors: Gunnar
authors: G
authors: Dittmar
authors: Thomas
authors: T
authors: Langer
authors: Mafalda
authors: M
authors: Escobar-Henriques
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D010450:Endopeptidases / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D010450:Endopeptidases; D046988:Proteasome Endopeptidase Complex; C059237:ubiquitin-Nalpha-protein hydrolase; C401395:FZO1 protein, S cerevisiae; D020558:GTP Phosphohydrolases; D008239:Lysine