USP8 and PARK2/parkin-mediated mitophagy
Identifieur interne : 000480 ( Main/Exploration ); précédent : 000479; suivant : 000481USP8 and PARK2/parkin-mediated mitophagy
Auteurs : Thomas M. Durcan ; Edward A. FonSource :
- Autophagy [ 1554-8627 ] ; 2015.
English descriptors
- KwdEn :
- Autophagy (physiology), Endopeptidases (metabolism), Endosomal Sorting Complexes Required for Transport (metabolism), Humans, Mitochondria (metabolism), Protein Processing, Post-Translational (physiology), Ubiquitin Thiolesterase (metabolism), Ubiquitin-Protein Ligases (metabolism), Ubiquitination (physiology).
- MESH :
- chemical , metabolism : Endopeptidases, Endosomal Sorting Complexes Required for Transport, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases.
- metabolism : Mitochondria.
- physiology : Autophagy, Protein Processing, Post-Translational, Ubiquitination.
- Humans.
Abstract
The Parkinson disease (PD)-associated E3-ubiquitin (Ub) ligase PARK2/parkin plays a central role in many stress response pathways, and in particular, in mitochondrial quality control. Within this pathway, PARK2 activation is accompanied by a robust increase in its autoubiquitination, followed by clearance of the damaged mitochondria by selective autophagy (mitophagy). Yet, little is known about how this auto-ubiquitination is regulated during mitophagy. In our study, we demonstrate that PARK2 forms predominantly K6-linked Ub conjugates on itself. Moreover, PARK2 interacts with the deubiquitinating enzyme USP8 that preferentially removes these K6-linked conjugates, thereby regulating the activity and function of PARK2 in the pathway. When USP8 is silenced, a persistence of K6-linked Ub conjugates on PARK2 delays both its translocation to damaged mitochondria and successful completion of mitophagy. Taken together, these findings implicate a novel role for K6-linked Ub conjugates and USP8-mediated deubiquitination in the regulation of PARK2 in mitochondrial quality control.
Url:
DOI: 10.1080/15548627.2015.1009794
PubMed: 25700639
PubMed Central: 4502724
Affiliations:
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Le document en format XML
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Durcan</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></analytic><series><title level="j">Autophagy</title><idno type="ISSN">1554-8627</idno><idno type="eISSN">1554-8635</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Autophagy (physiology)</term><term>Endopeptidases (metabolism)</term><term>Endosomal Sorting Complexes Required for Transport (metabolism)</term><term>Humans</term><term>Mitochondria (metabolism)</term><term>Protein Processing, Post-Translational (physiology)</term><term>Ubiquitin Thiolesterase (metabolism)</term><term>Ubiquitin-Protein Ligases (metabolism)</term><term>Ubiquitination (physiology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Endopeptidases</term><term>Endosomal Sorting Complexes Required for Transport</term><term>Ubiquitin Thiolesterase</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Autophagy</term><term>Protein Processing, Post-Translational</term><term>Ubiquitination</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The Parkinson disease (PD)-associated E3-ubiquitin (Ub) ligase PARK2/parkin plays a central role in many stress response pathways, and in particular, in mitochondrial quality control. Within this pathway, PARK2 activation is accompanied by a robust increase in its autoubiquitination, followed by clearance of the damaged mitochondria by selective autophagy (mitophagy). Yet, little is known about how this auto-ubiquitination is regulated during mitophagy. In our study, we demonstrate that PARK2 forms predominantly K6-linked Ub conjugates on itself. Moreover, PARK2 interacts with the deubiquitinating enzyme USP8 that preferentially removes these K6-linked conjugates, thereby regulating the activity and function of PARK2 in the pathway. When USP8 is silenced, a persistence of K6-linked Ub conjugates on PARK2 delays both its translocation to damaged mitochondria and successful completion of mitophagy. Taken together, these findings implicate a novel role for K6-linked Ub conjugates and USP8-mediated deubiquitination in the regulation of PARK2 in mitochondrial quality control.</p></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Durcan, Thomas M" sort="Durcan, Thomas M" uniqKey="Durcan T" first="Thomas M" last="Durcan">Thomas M. Durcan</name><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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