E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia

Monica Benini; Silvia Fortuni; Ivano Condò; Giulia Alfedi; Florence Malisan; Nicola Toschi; Dario Serio; Damiano Sergio Massaro; Gaetano Arcuri; Roberto Testi; Alessandra Rufini

doi:10.1016/j.celrep.2017.01.079

Cell Reports (Feb 2017)

E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia

Monica Benini,
Silvia Fortuni,
Ivano Condò,
Giulia Alfedi,
Florence Malisan,
Nicola Toschi,
Dario Serio,
Damiano Sergio Massaro,
Gaetano Arcuri,
Roberto Testi,
Alessandra Rufini

Affiliations

Monica Benini: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Silvia Fortuni: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Ivano Condò: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Giulia Alfedi: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Florence Malisan: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Nicola Toschi: Medical Physics Section, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Dario Serio: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Damiano Sergio Massaro: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Gaetano Arcuri: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Roberto Testi: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy
Alessandra Rufini: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, 00133 Rome, Italy

DOI: https://doi.org/10.1016/j.celrep.2017.01.079
Journal volume & issue: Vol. 18, no. 8
pp. 2007 – 2017

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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