Phosphorylation of NBR1 by GSK3 modulates protein aggregation
Identifieur interne : 000879 ( Main/Exploration ); précédent : 000878; suivant : 000880Phosphorylation of NBR1 by GSK3 modulates protein aggregation
Auteurs : Anne-Sophie Nicot [France] ; Francesca Lo Verso [Italie] ; Francesca Ratti [France] ; Fanny Pilot-Storck [France] ; Nathalie Streichenberger [France] ; Marco Sandri [Italie] ; Laurent Schaeffer [France] ; Evelyne Goillot [France]Source :
- Autophagy [ 1554-8627 ] ; 2014.
Abstract
The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation. Numerous neurodegenerative and neuromuscular diseases are associated with inappropriate aggregation of ubiquitinated proteins and GSK3 (glycogen synthase kinase 3) activity is involved in several of these proteinopathies. Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. Indeed, NBR1 phosphorylation decreases protein aggregation induced by puromycin or by the DES/desmin N342D mutant found in desminopathy patients and stabilizes ubiquitinated proteins. Importantly, decrease of protein aggregates is due to an inhibition of their formation and not to their autophagic degradation as confirmed by data on
Url:
DOI: 10.4161/auto.28479
PubMed: 24879152
PubMed Central: 4091167
Affiliations:
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Le document en format XML
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<series><title level="j">Autophagy</title>
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<front><div type="abstract" xml:lang="en"><p>The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation. Numerous neurodegenerative and neuromuscular diseases are associated with inappropriate aggregation of ubiquitinated proteins and GSK3 (glycogen synthase kinase 3) activity is involved in several of these proteinopathies. Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. Indeed, NBR1 phosphorylation decreases protein aggregation induced by puromycin or by the DES/desmin N342D mutant found in desminopathy patients and stabilizes ubiquitinated proteins. Importantly, decrease of protein aggregates is due to an inhibition of their formation and not to their autophagic degradation as confirmed by data on <italic>Atg7</italic>
knockout mice. The relevance of NBR1 phosphorylation in human pathology was investigated. Analysis of muscle biopsies of sporadic inclusion body myositis (sIBM) patients revealed a strong decrease of NBR1 phosphorylation in muscles of sIBM patients that directly correlated with the severity of protein aggregation. We propose that phosphorylation of NBR1 by GSK3 modulates the formation of protein aggregates and that this regulation mechanism is defective in a human muscle proteinopathy.</p>
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<author><name sortKey="Schmidt, B" uniqKey="Schmidt B">B Schmidt</name>
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<author><name sortKey="Lo Monte, F" uniqKey="Lo Monte F">F Lo Monte</name>
</author>
</analytic>
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</author>
<author><name sortKey="Doble, Bw" uniqKey="Doble B">BW Doble</name>
</author>
<author><name sortKey="Patel, S" uniqKey="Patel S">S Patel</name>
</author>
<author><name sortKey="Hansotia, T" uniqKey="Hansotia T">T Hansotia</name>
</author>
<author><name sortKey="Sinclair, Em" uniqKey="Sinclair E">EM Sinclair</name>
</author>
<author><name sortKey="Drucker, Dj" uniqKey="Drucker D">DJ Drucker</name>
</author>
<author><name sortKey="Nagy, A" uniqKey="Nagy A">A Nagy</name>
</author>
<author><name sortKey="Woodgett, Jr" uniqKey="Woodgett J">JR Woodgett</name>
</author>
</analytic>
</biblStruct>
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</author>
<author><name sortKey="Sandri, C" uniqKey="Sandri C">C Sandri</name>
</author>
<author><name sortKey="Gilbert, A" uniqKey="Gilbert A">A Gilbert</name>
</author>
<author><name sortKey="Skurk, C" uniqKey="Skurk C">C Skurk</name>
</author>
<author><name sortKey="Calabria, E" uniqKey="Calabria E">E Calabria</name>
</author>
<author><name sortKey="Picard, A" uniqKey="Picard A">A Picard</name>
</author>
<author><name sortKey="Walsh, K" uniqKey="Walsh K">K Walsh</name>
</author>
<author><name sortKey="Schiaffino, S" uniqKey="Schiaffino S">S Schiaffino</name>
</author>
<author><name sortKey="Lecker, Sh" uniqKey="Lecker S">SH Lecker</name>
</author>
<author><name sortKey="Goldberg, Al" uniqKey="Goldberg A">AL Goldberg</name>
</author>
</analytic>
</biblStruct>
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</author>
<author><name sortKey="Rasband, Ws" uniqKey="Rasband W">WS Rasband</name>
</author>
<author><name sortKey="Eliceiri, Kw" uniqKey="Eliceiri K">KW Eliceiri</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hara, T" uniqKey="Hara T">T Hara</name>
</author>
<author><name sortKey="Nakamura, K" uniqKey="Nakamura K">K Nakamura</name>
</author>
<author><name sortKey="Matsui, M" uniqKey="Matsui M">M Matsui</name>
</author>
<author><name sortKey="Yamamoto, A" uniqKey="Yamamoto A">A Yamamoto</name>
</author>
<author><name sortKey="Nakahara, Y" uniqKey="Nakahara Y">Y Nakahara</name>
</author>
<author><name sortKey="Suzuki Migishima, R" uniqKey="Suzuki Migishima R">R Suzuki-Migishima</name>
</author>
<author><name sortKey="Yokoyama, M" uniqKey="Yokoyama M">M Yokoyama</name>
</author>
<author><name sortKey="Mishima, K" uniqKey="Mishima K">K Mishima</name>
</author>
<author><name sortKey="Saito, I" uniqKey="Saito I">I Saito</name>
</author>
<author><name sortKey="Okano, H" uniqKey="Okano H">H Okano</name>
</author>
</analytic>
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</TEI>
<affiliations><list><country><li>France</li>
<li>Italie</li>
</country>
</list>
<tree><country name="France"><noRegion><name sortKey="Nicot, Anne Sophie" sort="Nicot, Anne Sophie" uniqKey="Nicot A" first="Anne-Sophie" last="Nicot">Anne-Sophie Nicot</name>
</noRegion>
<name sortKey="Goillot, Evelyne" sort="Goillot, Evelyne" uniqKey="Goillot E" first="Evelyne" last="Goillot">Evelyne Goillot</name>
<name sortKey="Pilot Storck, Fanny" sort="Pilot Storck, Fanny" uniqKey="Pilot Storck F" first="Fanny" last="Pilot-Storck">Fanny Pilot-Storck</name>
<name sortKey="Ratti, Francesca" sort="Ratti, Francesca" uniqKey="Ratti F" first="Francesca" last="Ratti">Francesca Ratti</name>
<name sortKey="Schaeffer, Laurent" sort="Schaeffer, Laurent" uniqKey="Schaeffer L" first="Laurent" last="Schaeffer">Laurent Schaeffer</name>
<name sortKey="Schaeffer, Laurent" sort="Schaeffer, Laurent" uniqKey="Schaeffer L" first="Laurent" last="Schaeffer">Laurent Schaeffer</name>
<name sortKey="Streichenberger, Nathalie" sort="Streichenberger, Nathalie" uniqKey="Streichenberger N" first="Nathalie" last="Streichenberger">Nathalie Streichenberger</name>
<name sortKey="Streichenberger, Nathalie" sort="Streichenberger, Nathalie" uniqKey="Streichenberger N" first="Nathalie" last="Streichenberger">Nathalie Streichenberger</name>
</country>
<country name="Italie"><noRegion><name sortKey="Lo Verso, Francesca" sort="Lo Verso, Francesca" uniqKey="Lo Verso F" first="Francesca" last="Lo Verso">Francesca Lo Verso</name>
</noRegion>
<name sortKey="Sandri, Marco" sort="Sandri, Marco" uniqKey="Sandri M" first="Marco" last="Sandri">Marco Sandri</name>
</country>
</tree>
</affiliations>
</record>
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