The NF-κB subunit RelB controls p100 processing by competing with the kinases NIK and IKK1 for binding to p100.
The heterodimer formed by the nuclear factor κB (NF-κB) subunits p52 and RelB is the product of noncanonical signaling in which the key event is the proteolytic processing of p100 to generate p52. The kinases NF-κB-inducing kinase (NIK) and inhibitor of κB kinase 1 (IKK1; also known as IKKα) are activated during noncanonical signaling and play essential roles in p100 processing. In resting cells, RelB remains associated with unprocessed p100 as a transcriptionally inert p100:RelB complex, which is part of a larger assembly with other NF-κB factors known as the "kappaBsome." We investigated how these two different RelB-containing complexes with opposing effects on target gene transcription are formed. We found that RelB controls the extent of both p100 processing and kappaBsome formation during noncanonical signaling. Within an apparently "transitional" complex that contains RelB, NIK, IKK1, and p100, RelB and the NIK:IKK1 complex competed with each other for binding to a region of p100. A fraction of p100 in the transitional complex was refractory to processing, which resulted in the formation of the kappaBsome. However, another fraction of p100 protein underwent NIK:IKK1-mediated phosphorylation and processing while remaining bound to RelB, thus forming the p52:RelB heterodimer. Our results suggest that changes in the relative concentrations of RelB, NIK:IKK1, and p100 during noncanonical signaling modulate this transitional complex and are critical for maintaining the fine balance between the processing and protection of p100.
Department of Chemistry and Biochemistry, University of California San Diego, San Diego, CA 92093, USA.
Amanda J
AJ
Fusco
Department of Chemistry and Biochemistry, University of California San Diego, San Diego, CA 92093, USA.
Anup
A
Mazumder
Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China.
Vivien Ya-Fan
VY
Wang
Department of Chemistry and Biochemistry, University of California San Diego, San Diego, CA 92093, USA.
Zhihua
Z
Tao
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Carl
C
Ware
Department of Chemistry and Biochemistry, University of California San Diego, San Diego, CA 92093, USA. gghosh@ucsd.edu.
Gourisankar
G
Ghosh
D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction / Q000502:physiology*; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D051841:Transcription Factor RelB; D000097782:NF-kappaB-Inducing Kinase; C498206:NFKB2 protein, human; C498207:Nfkb2 protein, mouse; C497593:RELB protein, human; C497594:Relb protein, mouse; C496559:CHUK protein, human; C496564:Chuk protein, mouse