title: The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation.
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.
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY10065, USA kah2015@med.cornell.edu.
authors.forename: Karin
authors.initials: K
authors.lastname: Hochrainer
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY10065, USA Instituto Gulbenkian de Ciência, Apartado 14, Oeiras, Portugal.
authors.forename: Nadja
authors.initials: N
authors.lastname: Pejanovic
authors.affiliation: Lehman College, City University of New York, Bronx, NY10468, USA.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Olaseun
authors.affiliation: Institute of Biotechnology and Life Sciences Biotechnologies, Cornell University, Ithaca, NY14853, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY10065, USA.
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY10065, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020134:Catalytic Domain; D002417:Cattle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; C107792:UBQLN1 protein, human; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; C406215:HERC3 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex