Feil Family Brain & Mind Research Institute

You are here

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

TitleThe ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation.
Publication TypeJournal Article
Year of Publication2015
AuthorsHochrainer K, Pejanovic N, Olaseun VA, Zhang S, Iadecola C, Anrather J
JournalNucleic Acids Res
Volume43
Issue20
Pagination9889-904
Date Published2015 Nov 16
ISSN1362-4962
KeywordsAnimals, Carrier Proteins, Catalytic Domain, Cattle, Cell Cycle Proteins, Cells, Cultured, DNA, DNA-Binding Proteins, HEK293 Cells, Humans, I-kappa B Proteins, NF-kappa B, NF-KappaB Inhibitor alpha, Proteasome Endopeptidase Complex, Protein Stability, Transcription Factor RelA, Transcription, Genetic, Ubiquitin-Protein Ligases, Ubiquitination
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.

DOI10.1093/nar/gkv1064
Alternate JournalNucleic Acids Res.
PubMed ID26476452
PubMed Central IDPMC4787756
Grant ListR01 HL077308 / HL / NHLBI NIH HHS / United States
R01 NS034179 / NS / NINDS NIH HHS / United States
HL077308 / HL / NHLBI NIH HHS / United States
NS34179 / NS / NINDS NIH HHS / United States