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Cell Rep. 2017 Feb 21;18(8):2007-2017. doi: 10.1016/j.celrep.2017.01.079.

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

Author information

1
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.
2
Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy.
3
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.
4
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.

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.

KEYWORDS:

E3 ligase; Friedreich ataxia; RNF126; frataxin; protein degradation; therapeutic target; ubiquitin

PMID:
28228265
PMCID:
PMC5329121
DOI:
10.1016/j.celrep.2017.01.079
[Indexed for MEDLINE]
Free PMC Article

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