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000140707 0247_ $$2doi$$a10.15252/embj.2018100730
000140707 0247_ $$2pmid$$apmid:30886048
000140707 0247_ $$2pmc$$apmc:PMC6484417
000140707 0247_ $$2ISSN$$a0261-4189
000140707 0247_ $$2ISSN$$a1460-2075
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000140707 037__ $$aDZNE-2020-07029
000140707 041__ $$aEnglish
000140707 082__ $$a570
000140707 1001_ $$avan Well, Eva M$$b0
000140707 245__ $$aA protein quality control pathway regulated by linear ubiquitination.
000140707 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2019
000140707 264_1 $$2Crossref$$3online$$bEMBO$$c2019-03-18
000140707 264_1 $$2Crossref$$3print$$bEMBO$$c2019-05-02
000140707 3367_ $$2DRIVER$$aarticle
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000140707 520__ $$aNeurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.
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000140707 536__ $$0G:(DE-HGF)POF3-341$$a341 - Molecular Signaling (POF3-341)$$cPOF3-341$$fPOF III$$x2
000140707 542__ $$2Crossref$$i2019-03-18$$uhttp://onlinelibrary.wiley.com/termsAndConditions#vor
000140707 542__ $$2Crossref$$i2019-03-18$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1
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000140707 650_7 $$2NLM Chemicals$$aHTT protein, human
000140707 650_7 $$2NLM Chemicals$$aHuntingtin Protein
000140707 650_7 $$2NLM Chemicals$$aNF-kappa B
000140707 650_7 $$2NLM Chemicals$$aSp1 Transcription Factor
000140707 650_7 $$2NLM Chemicals$$aSp1 protein, human
000140707 650_7 $$0120904-94-1$$2NLM Chemicals$$aPolyubiquitin
000140707 650_7 $$0EC 3.6.4.6$$2NLM Chemicals$$aValosin Containing Protein
000140707 650_2 $$2MeSH$$aAdult
000140707 650_2 $$2MeSH$$aAged
000140707 650_2 $$2MeSH$$aAnimals
000140707 650_2 $$2MeSH$$aBrain: metabolism
000140707 650_2 $$2MeSH$$aBrain: pathology
000140707 650_2 $$2MeSH$$aCase-Control Studies
000140707 650_2 $$2MeSH$$aCells, Cultured
000140707 650_2 $$2MeSH$$aEmbryo, Mammalian: cytology
000140707 650_2 $$2MeSH$$aEmbryo, Mammalian: metabolism
000140707 650_2 $$2MeSH$$aFemale
000140707 650_2 $$2MeSH$$aFibroblasts: cytology
000140707 650_2 $$2MeSH$$aFibroblasts: metabolism
000140707 650_2 $$2MeSH$$aHumans
000140707 650_2 $$2MeSH$$aHuntingtin Protein: genetics
000140707 650_2 $$2MeSH$$aHuntingtin Protein: metabolism
000140707 650_2 $$2MeSH$$aHuntington Disease: genetics
000140707 650_2 $$2MeSH$$aHuntington Disease: metabolism
000140707 650_2 $$2MeSH$$aHuntington Disease: pathology
000140707 650_2 $$2MeSH$$aMale
000140707 650_2 $$2MeSH$$aMice
000140707 650_2 $$2MeSH$$aMice, Knockout
000140707 650_2 $$2MeSH$$aMiddle Aged
000140707 650_2 $$2MeSH$$aNF-kappa B: genetics
000140707 650_2 $$2MeSH$$aNF-kappa B: metabolism
000140707 650_2 $$2MeSH$$aNeurons: metabolism
000140707 650_2 $$2MeSH$$aNeurons: pathology
000140707 650_2 $$2MeSH$$aPolyubiquitin: metabolism
000140707 650_2 $$2MeSH$$aProtein Binding
000140707 650_2 $$2MeSH$$aProtein Interaction Domains and Motifs
000140707 650_2 $$2MeSH$$aProtein Processing, Post-Translational
000140707 650_2 $$2MeSH$$aSignal Transduction
000140707 650_2 $$2MeSH$$aSp1 Transcription Factor: genetics
000140707 650_2 $$2MeSH$$aSp1 Transcription Factor: metabolism
000140707 650_2 $$2MeSH$$aUbiquitination
000140707 650_2 $$2MeSH$$aValosin Containing Protein: genetics
000140707 650_2 $$2MeSH$$aValosin Containing Protein: metabolism
000140707 7001_ $$aBader, Verian$$b1
000140707 7001_ $$aPatra, Maria$$b2
000140707 7001_ $$aSánchez-Vicente, Ana$$b3
000140707 7001_ $$aMeschede, Jens$$b4
000140707 7001_ $$aFurthmann, Nikolas$$b5
000140707 7001_ $$aSchnack, Cathrin$$b6
000140707 7001_ $$aBlusch, Alina$$b7
000140707 7001_ $$aLongworth, Joseph$$b8
000140707 7001_ $$aPetrasch-Parwez, Elisabeth$$b9
000140707 7001_ $$aMori, Kohji$$b10
000140707 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b11$$udzne
000140707 7001_ $$0P:(DE-HGF)0$$aTrümbach, Dietrich$$b12
000140707 7001_ $$aAngersbach, Lena$$b13
000140707 7001_ $$aShowkat, Cathrin$$b14
000140707 7001_ $$aSehr, Dominik A$$b15
000140707 7001_ $$aBerlemann, Lena A$$b16
000140707 7001_ $$aGoldmann, Petra$$b17
000140707 7001_ $$aClement, Albrecht M$$b18
000140707 7001_ $$aBehl, Christian$$b19
000140707 7001_ $$aWoerner, Andreas C$$b20
000140707 7001_ $$aSaft, Carsten$$b21
000140707 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b22$$udzne
000140707 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b23$$udzne
000140707 7001_ $$aEllrichmann, Gisa$$b24
000140707 7001_ $$aGold, Ralf$$b25
000140707 7001_ $$aDittmar, Gunnar$$b26
000140707 7001_ $$aHipp, Mark S$$b27
000140707 7001_ $$aHartl, F Ulrich$$b28
000140707 7001_ $$0P:(DE-HGF)0$$aTatzelt, Jörg$$b29
000140707 7001_ $$0P:(DE-2719)9000369$$aWinklhofer, Konstanze F$$b30$$eLast author$$udzne
000140707 77318 $$2Crossref$$3journal-article$$a10.15252/embj.2018100730$$b : EMBO, 2019-03-18$$n9$$tThe EMBO Journal$$v38$$x0261-4189$$y2019
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000140707 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484417
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000140707 9131_ $$0G:(DE-HGF)POF3-341$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lErkrankungen des Nervensystems$$vMolecular Signaling$$x2
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