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Inhibition of transcription by B Cell Leukemia 3 (Bcl-3) protein requires interaction with nuclear factor kB (NF-kB) p50
Collins, Patricia E.; Kiely, Patrick A.; Carmody, Ruaidhrí J.
B cell leukemia 3 (Bcl-3) is an essential negative regulator of NF- B during Toll-like receptor and TNF receptor signaling. Bcl-3 also interacts with a number of transcriptional regulators, including homodimers of the NF- B p50 subunit. Deletion of Bcl-3 results in increased NF- B p50 ubiquitination and proteasomal degradation and increased inflammatory gene expression. We employed immobilized peptide array technology to define a region of p50 required for the formation of a Bcl-3 p50 homodimer immunosuppressor complex. Our data demonstrate that amino acids 359–361 and 363 of p50 are critical for interaction with Bcl-3 and essential for Bcl-3-mediated inhibition of inflammatory gene expression. Bcl-3 is unable to interact with p50 when these amino acids are mutated, rendering it incapable of inhibiting the transcriptional activity of NF- B. Bcl-3 interaction-defective p50 is hyperubiquitinated and has a significantly reduced half-life relative to wild-type p50. Nfkb1 / cells reconstituted with mutated p50 precursor p105 are hyperresponsive to TNF stimulation relative to wild-type p105, as measured by inflammatory gene expression. Mutant p105 recapitulates a Bcl3 / phenotype. This study demonstrates that interaction with p50 is necessary and sufficient for the anti-inflammatory properties of Bcl-3 and further highlights the importance of p50 homodimer stability in the control of NF- B target gene expression. PUBLISHED peer-reviewed
Keyword(s): B cell leukemia 3 (Bcl-3)
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: University of Limerick
Citation(s): Journal of Biological Chemistry;289 (10), pp. 7059-7067
Publisher(s): American Society for Biochemistry and Molecular Biology
First Indexed: 2018-12-01 06:25:35 Last Updated: 2018-12-01 06:25:35