title: A novel mechanism of control of NFκB activation and inflammation involving A2B adenosine receptors.
abstract: The nuclear factor kappa B (NFκB) pathway controls a variety of processes, including inflammation, and thus, the regulation of NFκB has been a continued focus of study. Here, we report a newly identified regulation of this pathway, involving direct binding of the transcription factor NFκB1 (the p105 subunit of NFκB) to the C-terminus of the A(2B) adenosine receptor (A(2B)AR), independent of ligand activation. Intriguingly, binding of A(2B)AR to specific sites on p105 prevents polyubiquitylation and degradation of p105 protein. Ectopic expression of the A(2B)AR increases p105 levels and inhibits NFκB activation, whereas p105 protein levels are reduced in cells from A(2B)AR-knockout mice. In accordance with the known regulation of expression of anti- and pro-inflammatory cytokines by p105, A(2B)AR-null mice generate less interleukin (IL)-10, and more IL-12 and tumor necrosis factor (TNF-α). Taken together, our results show that the A(2B)AR inhibits NFκB activation by physically interacting with p105, thereby blocking its polyubiquitylation and degradation. Our findings unveil a surprising function for the A(2B)AR, and provide a novel mechanistic insight into the control of the NFκB pathway and inflammation.
authors: Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China.
authors: Ying
authors: Y
authors: Sun
authors: Yuanyuan
authors: Y
authors: Duan
authors: Anna S
authors: AS
authors: Eisenstein
authors: Wenbao
authors: W
authors: Hu
authors: Adrien
authors: A
authors: Quintana
authors: Wai Kwan
authors: WK
authors: Lam
authors: Yan
authors: Y
authors: Wang
authors: Zhenguo
authors: Z
authors: Wu
authors: Katya
authors: K
authors: Ravid
authors: Pingbo
authors: P
authors: Huang
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D010766:Phosphorylation; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D043704:Receptor, Adenosine A2B / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D052002:NF-kappa B p50 Subunit; D043704:Receptor, Adenosine A2B; D025821:Polyubiquitin