title: E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia.
abstract: Friedreich ataxia (FRDA) is a severe genetic neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. To date, there is no therapy to treat this condition. The amount of residual frataxin critically affects the severity of the disease; thus, attempts to restore physiological frataxin levels are considered therapeutically relevant. Frataxin levels are controlled by the ubiquitin-proteasome system; therefore, inhibition of the frataxin E3 ligase may represent a strategy to achieve an increase in frataxin levels. Here, we report the identification of the RING E3 ligase RNF126 as the enzyme that specifically mediates frataxin ubiquitination and targets it for degradation. RNF126 interacts with frataxin and promotes its ubiquitination in a catalytic activity-dependent manner, both in vivo and in vitro. Most importantly, RNF126 depletion results in frataxin accumulation in cells derived from FRDA patients, highlighting the relevance of RNF126 as a new therapeutic target for Friedreich ataxia.
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Fratagene Therapeutics Srl, Viale dei Campioni 8, 00144 Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Benini
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fortuni
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Condò
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Alfedi
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Florence
authors.initials: F
authors.lastname: Malisan
authors.affiliation: Medical Physics Section, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Toschi
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Fratagene Therapeutics Srl, Viale dei Campioni 8, 00144 Rome, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Serio
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Damiano Sergio
authors.initials: DS
authors.lastname: Massaro
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Arcuri
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Fratagene Therapeutics Srl, Viale dei Campioni 8, 00144 Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Testi
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy; Fratagene Therapeutics Srl, Viale dei Campioni 8, 00144 Rome, Italy. Electronic address: rufini@med.uniroma2.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufini
mesh_terms: D002384:Catalysis; D002460:Cell Line; D005621:Friedreich Ataxia / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D033862:Iron-Binding Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000096923:Frataxin; C578829:RNF126 protein, human
keywords: E3 ligase; Friedreich ataxia; RNF126; frataxin; protein degradation; therapeutic target; ubiquitin