The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation

Hochrainer, Karin; Pejanovic, Nadja; Olaseun, Victoria A.; Zhang, Sheng; Iadecola, Costantino; Anrather, Josef

Publication

The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation

2015-10-17Journal article

dc.contributor.author	Hochrainer, Karin
dc.contributor.author	Pejanovic, Nadja
dc.contributor.author	Olaseun, Victoria A.
dc.contributor.author	Zhang, Sheng
dc.contributor.author	Iadecola, Costantino
dc.contributor.author	Anrather, Josef
dc.date.accessioned	2015-12-16T15:33:56Z
dc.date.available	2015-12-16T15:33:56Z
dc.date.issued	2015-10-17
dc.description.abstract	Activation of NF-κB-dependent transcription represents an important hallmark of inflammation. While the acute inflammatory response is per se beneficial, it can become deleterious if its spatial and temporal profile is not tightly controlled. Classically, NF-κB activity is limited by cytoplasmic retention of the NF-κB dimer through binding to inhibitory IκB proteins. However, increasing evidence suggests that NF-κB activity can also be efficiently contained by direct ubiquitination of NF-κB subunits. Here, we identify the HECT-domain ubiquitin ligase HERC3 as novel negative regulator of NF-κB activity. We find that HERC3 restricts NF-κB nuclear import and DNA binding without affecting IκBα degradation. Instead HERC3 indirectly binds to the NF-κB RelA subunit after liberation from IκBα inhibitor leading to its ubiquitination and protein destabilization. Remarkably, the regulation of RelA activity by HERC3 is independent of its inherent ubiquitin ligase activity. Rather, we show that HERC3 and RelA are part of a multi-protein complex containing the proteasome as well as the ubiquitin-like protein ubiquilin-1 (UBQLN1). We present evidence that HERC3 and UBQLN1 provide a link between NF-κB RelA and the 26S proteasome, thereby facilitating RelA protein degradation. Our findings establish HERC3 as novel candidate regulating the inflammatory response initiated by NF-κB.	pt_PT
dc.description.sponsorship	American Heart Association Scientist Development: (SDG102600298), National Institute of Health Grants: (HL077308, NS34179), Funding for open access charge: NIH (NS34179).	pt_PT
dc.identifier.citation	Karin Hochrainer, Nadja Pejanovic, Victoria A. Olaseun, Sheng Zhang, Costantino Iadecola, and Josef Anrather The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation Nucl. Acids Res. (16 November 2015) 43 (20): 9889-9904 first published online October 17, 2015 doi:10.1093/nar/gkv1064	pt_PT
dc.identifier.doi	10.1093/nar/gkv1064	pt_PT
dc.identifier.uri	http://hdl.handle.net/10400.7/534
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.publisher	Oxford University Press	pt_PT
dc.relation.publisherversion	http://nar.oxfordjournals.org/content/43/20/9889.long	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	pt_PT
dc.subject	HERC3 protein, human	pt_PT
dc.title	The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation	pt_PT
dc.type	journal article
dspace.entity.type	Publication
oaire.citation.endPage	9904	pt_PT
oaire.citation.issue	20	pt_PT
oaire.citation.startPage	9889	pt_PT
oaire.citation.title	Nucleic Acids Research	pt_PT
oaire.citation.volume	43	pt_PT
rcaap.rights	openAccess	pt_PT
rcaap.type	article	pt_PT