TY - JOUR
T1 - Two Deubiquitylases Act on Mitofusin and Regulate Mitochondrial Fusion along Independent Pathways
AU - Anton, Fabian
AU - Dittmar, Gunnar
AU - Langer, Thomas
AU - Escobar-Henriques, Mafalda
N1 - Funding Information:
We would like to thank J. Nunnari for antibodies and for the plasmids Dnm1-GFP, pvt100-mtGFP, and pvt100-mtRFP; B. Westermann for the plasmid pYX142-mtGFP; and M. Hochstrasser for the plasmid YEp112-Myc-Ub. We are grateful to J. Dohmen for the strain YD466 and for stimulating discussions and to B. Daignan-Fornier and S. Hoppins for critical reading of the manuscript. We thank the CECAD mass spectrometry facility from the University of Cologne. This work was supported by grants of the Deutsche Forschungsgemeinschaft to M.E.-H. (ES 338/1-1) and to T.L. (SFB635, FOR885) and by a grant of the European Research Council (AdG number 233078) to T.L.
PY - 2013/2/7
Y1 - 2013/2/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84873433599&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2012.12.003
DO - 10.1016/j.molcel.2012.12.003
M3 - Article
C2 - 23317502
AN - SCOPUS:84873433599
SN - 1097-2765
VL - 49
SP - 487
EP - 498
JO - Molecular Cell
JF - Molecular Cell
IS - 3
ER -